2024/06/25 更新

写真a

マルヤマ サトシ
丸山 智
MARUYAMA Satoshi
所属
医歯学総合病院 口腔外科系歯科 顎顔面口腔外科 講師
医歯学総合研究科 口腔生命科学専攻 講師
職名
講師
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外部リンク

学位

  • 歯学博士「歯学」 ( 2004年3月   新潟大学 )

研究キーワード

  • 口腔病理学

  • 唾液腺腫瘍

  • 低酸素

  • 口腔がん

研究分野

  • ライフサイエンス / 病態系口腔科学

経歴(researchmap)

  • 新潟大学   医歯学総合病院   講師(歯科病理検査室)

    2009年2月 - 現在

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  • 新潟大学   大学院医歯学総合研究科   助教(口腔病理学)

    2005年5月 - 2009年1月

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  • 新潟大学   大学院医歯学総合研究科   科学研究費研究員(口腔病理学分野)

    2004年5月 - 2005年4月

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  • 浜松医科大学   歯科口腔外科   研修医

    1999年5月 - 2000年3月

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経歴

  • 新潟大学   医歯学総合病院 口腔外科系歯科   講師

    2012年11月 - 現在

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻   講師

    2009年2月 - 現在

  • 新潟大学   口腔外科   講師

    2009年2月 - 2012年11月

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻   助教

    2005年5月 - 2009年1月

  • 新潟大学   医歯学総合研究科   研究員

    2004年5月 - 2005年4月

学歴

  • 新潟大学   大学院歯学研究科博士課程   (口腔病理学講座)

    2000年4月 - 2004年3月

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    国名: 日本国

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  • 新潟大学   歯学部   歯

    1993年4月 - 1999年3月

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    国名: 日本国

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所属学協会

 

論文

  • Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication 査読

    Shinsuke Fujii, Kana Hasegawa, Takashi Maehara, Kari J Kurppa, Kristiina Heikinheimo, Kristy A. Warner, Satoshi Maruyama, Yudai Tajiri, Jacques E. Nör, Jun-ichi Tanuma, Shintaro Kawano, Tamotsu Kiyoshima

    Pathology - Research and Practice   155148 - 155148   2024年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.prp.2024.155148

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  • Comparing the Diagnostic Accuracy of Ultrasonography, CT, MRI, and PET/CT in Cervical Lymph Node Metastasis of Oral Squamous Cell Carcinoma

    Masaki Takamura, Yutaka Nikkuni, Takafumi Hayashi, Kouji Katsura, Hideyoshi Nishiyama, Manabu Yamazaki, Satoshi Maruyama, Jun-ichi Tanuma

    Biomedicines   11 ( 12 )   3119 - 3119   2023年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    (1) Background: In oral cancer staging, ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[fluorine-18]fluoro-D-glucose (FDG) with positron emission tomography/computed tomography (PET/CT) are routinely used in clinical practice. The present study is a retrospective examination of the diagnostic accuracy of cervical lymph node metastasis using US, CT, MRI, and PET/CT, with histopathological diagnosis as a reference, to compare the different diagnostic imaging modalities. (2) Methods: The participants included 16 patients with oral squamous cell carcinoma who underwent US-, CT-, MRI-, and PET/CT-based preoperative diagnostic imaging and simultaneous primary lesion resection and neck dissection, including 82 level regions and 424 lymph nodes. We compared the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of each imaging modality based on the imaging results and the pathology results of metastasis. (3) Results: Of the four diagnostic imaging modalities, PET/CT exhibited the highest sensitivity but the lowest specificity and accuracy. US, CT, and MRI had high specificities. Comparing each level region and lymph node showed that differences were observed in PET/CT. (4) Conclusions: PET/CT to diagnose lymph node metastasis requires a comprehensive evaluation because it produces more false positives than other diagnostic imaging modalities. Using US, CT, and MRI, which have excellent spatial resolution, improves diagnostic accuracy at the lymph node level.

    DOI: 10.3390/biomedicines11123119

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  • Hypoxia-Induced Biosynthesis of the Extracellular Matrix Molecules, Perlecan and Fibronectin, Promotes the Growth of Pleomorphic Adenoma Cells In Vitro Models 査読

    Satoshi Maruyama, Manabu Yamazaki, Tatsuya Abé, Jun Cheng, Takashi Saku, Jun-ichi Tanuma

    Biomedicines   11 ( 11 )   2981 - 2981   2023年11月

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    担当区分:筆頭著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Salivary pleomorphic adenoma is histopathologically characterized by its colorful stroma with myxoid, chondroid, and hyaline appearances, due to enhanced biosynthesis of extracellular matrix (ECM) molecules and poor vascularity. Thus, pleomorphic adenoma cells embedded in the stroma typically survive under hypoxic conditions. We determined the expression kinetics of ECM molecules, such as perlecan and fibronectin (FN), under hypoxia in SM-AP1 cells which are duct epithelial differentiated cells, and in SM-AP4 cells, which are myoepithelial differentiated cells, cloned from pleomorphic adenoma of the parotid gland. We investigated hypoxia-inducible factor-1α (HIF-1α)-inducing pathways through a variety of ECM molecules in association with their cellular proliferation and migration. We observed that hypoxic conditions with elevated HIF-1α protein levels induced increased expression of perlecan and FN in SM-AP cells than in controls. Moreover, perlecan and FN knockdown reduced the proliferation of SM-AP1 and SM-AP4 cells under hypoxia. Further, SM-AP1 cell migration was enhanced by both perlecan and FN knockdown, whereas SM-AP4 cell migration was increased by perlecan knockdown and inhibited by fibronectin knockdown. The results indicated that pleomorphic adenoma cells can survive under hypoxic conditions by promoting cell proliferation via enhanced synthesis of ECM molecules. Overall, ECM molecules may be a new anti-tumor target under hypoxic conditions.

    DOI: 10.3390/biomedicines11112981

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  • Searching for new early detection markers of oral epithelial dysplasia and oral squamous cell carcinoma using oral liquid-based cytology

    Toshiyuki Akimori, Manabu Yamazaki, Tatsuya Abé, Satoshi Maruyama, Kei Tomihara, Takeyasu Maeda, Jun-ichi Tanuma

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   2023年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.ajoms.2023.11.007

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  • 光干渉断層撮影を用いた3次元口腔癌モデルにおける癌浸潤の定量解析(Quantitative analysis of cancer cell invasion on 3D in vitro oral cancer models using optical coherence tomography)

    羽賀 健太, 山崎 学, 丸山 智, 阿部 達也, 小林 正治, 田沼 順一

    日本癌学会総会記事   82回   970 - 970   2023年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • Masticatory muscle tendon-aponeurosis hyperplasia that was initially misdiagnosed for polymyositis: a case report and review of the literature

    Wataru Katagiri, Daisuke Saito, Satoshi Maruyama, Makiko Ike, Hideyoshi Nisiyama, Takafumi Hayashi, Jun-ichi Tanuma, Tadaharu Kobayashi

    Maxillofacial Plastic and Reconstructive Surgery   45 ( 1 )   2023年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    Background

    Masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) is a relatively newly identified clinical condition that manifests as trismus with a square-shaped mandible. Herein, we report a case of MMATH that was initially misdiagnosed for polymyositis due to trismus and simultaneous lower limb pain, with literature review.

    Case presentation

    A 30-year-old woman had a history of lower limb pain after exertion for 2 years. Initial physical examination had been performed at the Department of General Medicine in our hospital. There was also redness in the hands and fingers. Although polymyositis was suspected, it was denied. The patient visited our department for right maxillary wisdom tooth extraction.

    Clinical examination revealed that the patient had a square-shaped mandible. The maximal mouth opening was 22 mm. There was no temporomandibular joint pain at the time of opening. Furthermore, there was awareness of clenching while working. Panoramic radiography revealed developed square mandibular angles with flattened condyles. Computed tomography showed enlarged masseter muscles with high-density areas around the anterior and lateral fascia. Magnetic resonance imaging also showed thickened tendons and aponeuroses on the anterior surface and inside bilateral masseter muscles. Finally, the patient was diagnosed with MMTAH. Bilateral aponeurectomy of the masseter muscles with coronoidectomy and masseter muscle myotomy was performed under general anesthesia. The maximum opening during surgery was 48 mm. Mouth opening training was started on day 3 after surgery. Histopathological examination of the surgical specimen showed that the muscle fibers were enlarged to 60 μm. Immunohistochemistry testing for calcineurin, which was associated with muscle hypertrophy due to overload in some case reports, showed positive results. Twelve months after surgery, the mouth self-opening and forced opening were over 35 mm and 44 mm, respectively.

    Conclusions

    Herein, we report a case of MMATH. Lower limb pain due to prolonged standing at work and overload due to clenching were considered risk factors for symptoms onset of MMATH.

    DOI: 10.1186/s40902-023-00386-6

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    その他リンク: https://link.springer.com/article/10.1186/s40902-023-00386-6/fulltext.html

  • Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma 招待 査読

    Nyein Nyein Chan, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Kenta Haga, Masami Kawaharada, Kenji Izumi, Tadaharu Kobayashi, Jun-ichi Tanuma

    International Journal of Molecular Sciences   24 ( 7 )   6035   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3390/ijms24076035

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  • Liquid‐based cytology for differentiating two cases of pemphigus vulgaris from oral squamous cell carcinoma 査読 国際誌

    Maruyama S, Yamazaki M, Abé T, Kato Y, Kano H, Sumita Y, Tomihara K, Tanuma J

    Diagnostic Cytopathology   51 ( 5 )   1 - 6   2023年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pemphigus vulgaris (PV) is a rare autoimmune disease characterized by blisters on the skin and mucous membrane. Since it often appears in the oral mucosa first, it may be diagnosed by oral mucosal cytology. Although the cytologic finding is characterized by acantholytic cells, that is, Tzanck cells, it is important to distinguish PV from neoplastic lesions of the oral mucosal epithelium, including differentiation from atypical parabasal/basal cells, which appear in squamous cell carcinoma (SCC). In this study, we examined the cellular findings in two cases of PV and a case of well-differentiated SCC with loss of epithelial cell cohesion. The samples were prepared using liquid-based cytology, which showed small round-shaped and deeply stained atypical, orangeophilic keratinocytes not only in SCC but also in PV, which made differentiation between the two difficult. However, Tzanck cells found in PV differ from the deep atypical parabasal/basal cells of SCC, suggesting that the cell outline is indistinct and small protrusions and brush-like structures are observed. This feature of Tzanck cells may be useful in cytological judgment.

    DOI: 10.1002/dc.25117

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  • 口底部に生じた異所性胃腸管嚢胞の1例

    齋藤 直朗, 丸山 智, 加藤 祐介, 竹内 涼子, 田沼 順一, 小林 正治

    日本口腔外科学会雑誌   69 ( 1 )   27 - 31   2023年1月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

    4歳5ヵ月女児。既往として出生前診断で指摘されていた口底部の嚢胞様病変に対し、生後3日に開窓術が施行され、病理組織学的に類表皮嚢胞と診断された。今回、3歳9ヵ月時に開窓部からの出血を主訴に当科へ受診となった。数日後に出血が治まったため、いったん終診となったが、4歳2ヵ月頃より唾仙痛様症状が出現したため再診した。口腔内所見および画像所見を踏まえて、開窓術後の変化を伴う口底部類表皮嚢胞と診断され、5歳時に全身麻酔下で嚢胞摘出術が行われた。その結果、病理組織学的に異所性胃腸管嚢胞と確定診断された。術後3年経過現在、再発なく、経過良好である。

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01073&link_issn=&doc_id=20230201450005&doc_link_id=10.5794%2Fjjoms.69.27&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.69.27&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • Adenosquamous Carcinoma with the Acantholytic Feature in the Oral Cavity: A Case Report and Comprehensive Literature Review

    Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Nobuyuki Ikeda, Yoshimasa Sumita, Kei Tomihara, Jun-ichi Tanuma

    Diagnostics   12 ( 10 )   2398 - 2398   2022年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Adenosquamous carcinoma (ASC) is an aggressive subtype of squamous cell carcinoma (SCC). Due to its poor prognosis, a precise pathological diagnosis of ASC is essential but challenging because its pathological criteria are still unclear. Here, we present a rare case of oral ASC accompanied by acantholytic features. The tumor was raised in the mandibular gingiva and recurred locally approximately 13 months after the initial surgery with cervical lymph node metastasis. Pathological specimens of the primary lesion showed acantholysis in a large area of the SCC. Mucous cells, the characteristic finding indicating glandular differentiation, were imperceptible in the initial surgical specimen but increased in the locally recurrent and metastatic lymph node specimens. In a comprehensive literature review of oral ASC cases, the present case was the only case of ASC with acantholytic features. We reconfirmed that ASC has poor prognoses, such as low 5-year overall survival and disease-free survival, high locoregional recurrence, and high distant metastasis rates. A precise diagnosis of ASC is required for estimating prognosis and undergoing close follow-up, even if the adenocarcinomatous component is limited to a small area in the lesion.

    DOI: 10.3390/diagnostics12102398

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  • Clinicopathologic factors influencing the screening accuracy of oral cytology: A retrospective cohort study 査読 国際誌

    MASAMI KAWAHARADA, SATOSHI MARUYAMA, MANABU YAMAZAKI, TATSUYA ABÉ, NYEIN NYEIN CHAN, AKINORI FUNAYAMA, ATSUSHI UENOYAMA, TOSHIYUKI AKIMORI, KEI TOMIHARA, JUN-ICHI TANUMA

    Oncology letters   24 ( 385 )   385 - 385   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cytology is a simple and non-invasive screening method for oral cancer. However, this method is not yet routinely used by clinicians because of its high false negative rate (FNR) and due to lack of sufficient studies examining the factors for high FNRs. The present retrospective study aimed to compare the screening performance of conventional cytology (CC) and liquid-based cytology (LBC) through histological validation, and to elucidate factors inducing false negative screening in oral cytology. Cytological specimens with histological examination and intraoral digital images of the lesion were retrospectively collected between January 2017 and December 2018 for CC and between October 2019 and September 2021 for LBC. Oral cytological screening was conducted based on the oral Bethesda system for oral cytology. Clinical subtypes were re-evaluated using intraoral digital images. The screening accuracy of oral cytology was calculated considering the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting the malignant transformation of oral lesions. No statistically significant difference was noted in the inadequate rate between CC and LBC groups. For CC and LBC, the sensitivities were 60.9 and 59.2%, the specificities were 87.3 and 79.1%, the PPVs were 85.8 and 76.2%, and the NPVs were 63.9 and 63.2%, respectively. Thus, the screening accuracy was similar between methodologies. Among the clinicopathological factors investigated, histological diagnosis and cellularity contributed to false negative results. Homogeneous findings of oral epithelial dysplasia and the superficial growth of carcinoma in situ/squamous cell carcinoma resulted in false negative findings for CC and LBC. Furthermore, LBC samples with a lower cell number (<2,000 squamous cells) exhibited statistically significantly increased FNRs. The present study found that the cytological methods did not affect the inadequate rate and screening accuracy, whereas clinical subtype and cellularity decreased screening accuracy. Therefore, cytological screening and subsequent follow-up should be performed while considering clinical findings and the cellularity of cytology smears.

    DOI: 10.3892/ol.2022.13505

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  • 下顎歯肉部転移性腫瘍を契機に診断に至った膵癌の1例

    須田 大亮, 船山 昭典, 齋藤 大輔, 新國 農, 丸山 智, 林 孝文, 田沼 順一, 小林 正治

    日本口腔科学会雑誌   71 ( 2 )   159 - 159   2022年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • Novel cytological model for the identification of early oral cancer diagnostic markers: The carcinoma sequence model. 国際誌

    Masami Kawaharada, Manabu Yamazaki, Satoshi Maruyama, Tatsuya AbÉ, Nyein Nyein Chan, Taiichi Kitano, Tadaharu Kobayashi, Takeyasu Maeda, Jun-Ichi Tanuma

    Oncology letters   23 ( 3 )   76 - 76   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Most oral squamous cell carcinomas (OSCCs) arise from a premalignant lesion, oral epithelial dysplasia; however, useful markers for the early detection of OSCC are lacking. The present study aimed to establish a novel experimental model to observe changes in the sequential expression patterns of mRNAs and proteins in a rat model of tongue cancer using liquid-based cytology techniques. Cytology specimens were collected at 2, 5, 8, 11, 14, 17 and 21 weeks from rats treated with 4-nitroquinoline 1-oxide to induce tongue cancer. The expression of candidate biomarkers was examined by performing immunocytochemistry and reverse transcription-quantitative PCR. The percentage of positively stained nuclei was calculated as the labeling index (LI). All rats developed OSCC of the tongue at 21 weeks. The mRNA expression levels of bromodomain protein 4 (Brd4), c-Myc and Tp53 were upregulated during the progression from negative for intraepithelial lesion or malignancy to squamous cell carcinoma (SCC). Brd4- and c-Myc-LI increased in low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion and SCC specimens. p53-LI was significantly increased in SCC specimens. This novel experimental model allowed the observation of sequential morphological changes and the expression patterns of mRNAs and proteins during carcinogenesis. Combining immunocytochemistry with cytology-based diagnoses may potentially improve the diagnostic accuracy of OSCC.

    DOI: 10.3892/ol.2022.13196

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  • コレステロールは口腔扁平上皮癌細胞の極性を制御し遊走を促進する(Cholesterol assists migration of oral squamous cell carcinoma by regulating front-rear cell polarity)

    チャン・ニェインニェイン, 山崎 学, 丸山 智, 阿部 達也, 河原田 壮史, 小林 正治, 田沼 順一

    日本病理学会会誌   111 ( 1 )   278 - 278   2022年3月

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    記述言語:英語   出版者・発行元:(一社)日本病理学会  

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  • Metastasis of pulmonary adenocarcinoma to the oral cavity: A case report and literatures review of the last 30 years

    Masami Kawaharada, Satoshi Maruyama, Tatsuya Abé, Takafumi Hayashi, Tadaharu Kobayashi, Jun‐ichi Tanuma

    Oral Science International   2022年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/osi2.1130

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/osi2.1130

  • 広範な口腔潰瘍を契機に診断に至った多発血管炎性肉芽腫症の1例

    須田 大亮, 竹内 玄太郎, 丸山 智, 小林 正治, 加納 浩之

    日本口腔外科学会雑誌   68 ( 1 )   8 - 14   2022年1月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

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  • Melanotic neuroectodermal tumor of infancy in the mandible: A case report. 国際誌

    Ryoko Takeuchi, Akinori Funayama, Yohei Oda, Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Takafumi Hayashi, Jun-Ichi Tanuma, Tadaharu Kobayashi

    Medicine   100 ( 50 )   e28001   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RATIONALE: Melanocytic neuroectodermal tumor of infancy (MNTI) is a rare benign pigmented neoplasm that arises from the neural crest and has an aggressive growth pattern. It is predominantly seen in infants under 1 year of age, and the most common site of involvement is the maxilla. The currently accepted treatment is removal by surgical resection. Herein, we report a case of MNTI that involved the anterior alveolar ridge of the mandible in a 6-month-old infant. PATIENT CONCERNS: A case of a 6-month-old male child with a huge mass in the anterior alveolar ridge of the mandible. DIAGNOSIS: The tumor was diagnosed using histopathological and immunohistochemical techniques on the biopsy specimen obtained following incisional biopsy. Based on the findings, a final diagnosis of MNTI was established. INTERVENTIONS: Radical resection of the tumor was performed, after determining the extent of resection by referring to the mandibular 3D model created using the pre-operative CT data. OUTCOMES: The postoperative course was uneventful, and no recurrence has been observed to date for more than 4 years after surgery. LESSONS: This case emphasizes that early diagnosis and radical surgery are critical to the effective treatment, as MNTI exhibits rapid and destructive growth. It also requires careful and close follow-up because of high recurrence rates.

    DOI: 10.1097/MD.0000000000028001

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  • Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression

    Kenta Haga, Manabu Yamazaki, Satoshi Maruyama, Masami Kawaharada, Ayako Suzuki, Emi Hoshikawa, Nyein Nyein Chan, Akinori Funayama, Toshihiko Mikami, Tadaharu Kobayashi, Kenji Izumi, Jun-ichi Tanuma

    Translational Oncology   14 ( 12 )   101236 - 101236   2021年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.tranon.2021.101236

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  • 口腔領域に発症したOI-LPD4例の臨床病理学的検討と最近15年間の文献的考察

    河原田 壮史, 丸山 智, 山崎 学, 阿部 達也, 黒川 亮, 片桐 渉, 林 孝文, 高木 律男, 小林 正治, 田沼 順一

    新潟歯学会雑誌   51 ( 2 )   114 - 115   2021年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 口腔がん早期診断用マーカーの同定に向けた新規発がんモデルの作製

    河原田 壮史, 山崎 学, 丸山 智, 阿部 達也, 北野 太一, Chan Nyein Nyein, 小林 正治, 田沼 順一

    新潟歯学会雑誌   51 ( 2 )   124 - 124   2021年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Spindle cell squamous cell carcinoma exhibiting prominent neutrophil phagocytosis: a case report. 国際誌

    Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Yoshimasa Sumita, Yuji Katsumi, Yutaka Nikkuni, Takafumi Hayashi, Jun-Ichi Tanuma

    Journal of medical case reports   15 ( 1 )   438 - 438   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Spindle cell squamous cell carcinoma is an uncommon variant of squamous cell carcinoma; its diagnosis is sometimes challenging because it histopathologically resembles neoplastic or reactive spindle cell lesions of mesenchymal origins. Here, we report a rare case of spindle cell squamous cell carcinoma exhibiting prominent neutrophil phagocytosis. CASE PRESENTATION: A 69-year-old Japanese man presented with pain and a polypoid mass on the lower left gingiva. He had received chemoradiotherapy for squamous cell carcinoma of the buccal mucosa 15 years prior to this consultation. In addition, he was treated for mandibular osteonecrosis 6 years after chemoradiotherapy without evidence of cancer recurrence. A biopsy revealed atypical spindle or pleomorphic cells scattered in the edematous and fibrin-rich stroma; however, no malignant squamous components were apparent. These atypical cells frequently contained neutrophils within their cytoplasm that formed cell-in-cell figures. Immunohistochemically, the atypical cells were negative for cytokeratins, epithelial membrane antigen, and E-cadherin, but positive for p63, vimentin, and p53. Although these findings suggested spindle cell squamous cell carcinoma, it was difficult to reach a definitive diagnosis. Based on a clinical diagnosis of a malignant tumor, the patient underwent a hemimandibulectomy. The surgically resected specimen had a typical spindle cell squamous cell carcinoma histology consisting of biphasic spindle cells and conventional squamous cell carcinoma components. Moreover, the surgical specimen also exhibited spindle tumor cells that frequently included neutrophils, around which intense staining for lysosomal-associated membrane protein 1 and cathepsin B was observed. This suggested that the cell-in-cell figures represent active neutrophil phagocytosis by tumor cells, and not emperipolesis. CONCLUSION: The presence of neutrophil phagocytosis may be a potent indicator of malignancy.

    DOI: 10.1186/s13256-021-03066-z

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  • Central mucoepidermoid carcinoma arising directly from a glandular odontogenic cyst of the mandible: a case report. 査読 国際誌

    Satoshi Maruyama, Taisuke Mori, Manabu Yamazaki, Tatsuya Abé, Eijitsu Ryo, Hiroyuki Kano, Go Hasegawa, Jun-Ichi Tanuma

    Diagnostic pathology   16 ( 1 )   61 - 61   2021年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Central mucoepidermoid carcinoma (MEC) is a rare salivary gland tumor that affects the jawbone. Glandular odontogenic cyst (GOC) is also a rare odontogenic developmental cyst with glandular differentiation. GOC shares some histological features with central MEC, and a pre-existing GOC can develop into central MEC. Here, we present a rare case of central MEC developed directly from a pre-existing GOC of the mandible. CASE PRESENTATION: A 67-year-old Japanese man presented with a cystic lesion in the right third molar region. Histologically, the biopsy specimen demonstrated both typical findings of a GOC component lined with non-keratinized squamous epithelium and a recognizable component of central MEC consisting of polycystic nests with mucous cells, intermediate cells, and epidermoid cells in the cyst wall. The results from the immunohistochemistry for cytokeratin (CK) profiling demonstrated that, while both central MEC and GOC expressed CKs 7, 14, 18, and 19, CK13 was interestingly exclusively expressed in GOC. Fluorescence in-situ hybridization (FISH) revealed the rearrangement of the Mastermind like (MAML)-2 gene in both the MEC and GOC components. CONCLUSIONS: Our case suggests that central MEC and GOC may be in the same spectrum of diseases caused by the rearrangement of the MAML-2 gene. However, given that the expression profile of CK13 was completely different between central MEC and GOC, they can be considered as separate tumors. Overall, we demonstrated a rare case in which central MEC may have originated directly from the GOC.

    DOI: 10.1186/s13000-021-01124-0

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  • 口腔領域に発症したOI-LPDの臨床病理学的解析

    河原田 壮史, 丸山 智, 山崎 学, 阿部 達也, 黒川 亮, 片桐 渉, 林 孝文, 高木 律男, 小林 正治, 田沼 順一

    日本口腔科学会雑誌   70 ( 2 )   147 - 147   2021年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • Other iatrogenic immunodeficiency-associated lymphoproliferative disorders in the oral cavity: a clinicopathologic study of 4 cases and literature review. 国際誌

    Masami Kawaharada, Satoshi Maruyama, Tatsuya Abé, Manabu Yamazaki, Akira Kurokawa, Wataru Katagiri, Ritsuo Takagi, Takafumi Hayashi, Tadaharu Kobayashi, Jun-Ichi Tanuma

    Oral surgery, oral medicine, oral pathology and oral radiology   132 ( 6 )   687 - 697   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OI-LPD) have been reported as one of the adverse effects of immunosuppressive therapy. The aim of this study was to describe the clinicopathologic and immunohistochemical features of OI-LPD in the oral cavity. STUDY DESIGN: Immunohistochemistry was performed to describe the immunohistochemical features in our 4 cases. The results were analyzed along with 62 cases of oral OI-LPD in the English and Japanese literature to define clinical and pathologic characteristic features. RESULTS: In our immunohistochemical analysis, Epstein-Barr virus (EBV)-positive OI-LPD showed a higher percentage of mouse double minute 2-positive cells than EBV-negative samples. A literature survey revealed that OI-LPD (including the present cases) arises primarily in the gingiva, followed by the tongue, and usually occurs with a male-to-female ratio of 1:1.9. The rate of EBV positivity was 93.8%. Further, 31 of 66 patients had osteonecrosis of the jaw and 24 of 31 patients had taken multiple immunosuppressive drugs in combination. CONCLUSIONS: We can therefore conclude that the overexpression of mouse double minute 2 in OI-LPD is associated with EBV infection, and the combination of multiple immunosuppressive drugs may be a risk factor for osteonecrosis of the jaw.

    DOI: 10.1016/j.oooo.2021.05.015

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  • A comparative study between CT, MRI, and intraoral US for the evaluation of the depth of invasion in early stage (T1/T2) tongue squamous cell carcinoma

    Masaki Takamura, Taichi Kobayashi, Yutaka Nikkuni, Kouji Katsura, Manabu Yamazaki, Satoshi Maruyama, Jun-ichi Tanuma, Takafumi Hayashi

    Oral Radiology   38 ( 1 )   114 - 125   2021年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title><sec>
    <title>Objectives</title>
    This study aimed to clarify the accuracy of intraoral ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) in preoperative image depth of invasion (DOI) measurement of T1/T2 tongue cancer through comparison with histopathological measurements.


    </sec><sec>
    <title>Methods</title>
    Imaging of the primary lesions was performed at our hospital; the lesions were classified into T1 and T2 based on the 8th edition of the AJCC/UICC, and surgery performed. There was histopathological confirmation of lesions as squamous cell carcinoma in 48 patients with tongue cancer. T3 and T4 cases, cases in which preoperative chemotherapy and radiation therapy were performed, and cases where biopsy was performed before imaging were excluded. The radiological DOI in US, CT, and MRI and the histopathological DOI as base were comparatively investigated and statistical analyses were performed by Bland–Altman analysis and Spearman's rank correlation coefficient.


    </sec><sec>
    <title>Results</title>
    Bland–Altman analysis showed that the US radiological DOI was overestimated by an average of 0.2 mm compared to the histopathological DOI, while CT and MRI radiological DOI were overestimated by an average of 2–3 mm. The comparison of CT and MRI revealed that the difference between the MRI and histopathological DOI, as well as the 95% limit of agreement, were smaller than those of the CT radiological DOI.


    </sec><sec>
    <title>Conclusions</title>
    US is the most accurate preoperative diagnostic tool for T1 and T2 squamous cell carcinoma; CT and MRI tend to have an overestimation of about 2–3 mm and so caution is required.


    </sec>

    DOI: 10.1007/s11282-021-00533-7

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    その他リンク: https://link.springer.com/article/10.1007/s11282-021-00533-7/fulltext.html

  • Keratin 17-positive Civatte bodies in oral lichen planus—distribution variety, diagnostic significance and histopathogenesis

    Tatsuya Abé, Norio Kitagawa, Shohei Yoshimoto, Satoshi Maruyama, Manabu Yamazaki, Tetsuichiro Inai, Shuichi Hashimoto, Takashi Saku

    Scientific Reports   10 ( 1 )   2020年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1038/s41598-020-71496-8

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    その他リンク: http://www.nature.com/articles/s41598-020-71496-8

  • 下顎埋伏智歯に関連した原発性骨内癌の1例

    小林 亮太, 高木 律男, 新國 農, 丸山 智, 山崎 学, 上野山 敦士, 田沼 順一, 林 孝文, 児玉 泰光

    日本口腔腫瘍学会誌   32 ( 4 )   243 - 250   2020年12月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔腫瘍学会  

    かかりつけ歯科医院での長期メインテナンス中、下顎埋伏智歯の歯冠部に関連して生じたと考えられる高齢者の原発性骨内癌を経験したので報告する。症例は74歳の男性、右側下唇の知覚異常と右側下顎臼歯部の咬合痛を主訴に当科紹介初診となった。右側下顎第二大臼歯は挺出し、動揺度2、頬側歯肉に軽度の腫脹を認めたが排膿はなかった。パノラマX線写真で右側下顎智歯は骨性に逆生埋伏しており、単純CTで埋伏智歯の歯冠部に連続した境界不明瞭で辺縁不整な35×25mm大の腫瘤性病変を認めた。生検にて扁平上皮癌(原発性骨内癌疑い)の診断を得て、顎下部郭清術、下顎骨区域切除術、金属プレートによる顎骨再建術を行った。一般的に原発性骨内癌は嚢胞様病変から悪性転化するとされるが、本症例は当科初診の8ヵ月前に紹介元で撮影されたパノラマX線写真では異常所見は観察されず、明白な嚢胞様変化を辿ることなく悪性転化し、急速に増大したと推察された。症状のない下顎埋伏智歯は経過観察されることが多いが、発育性嚢胞や歯周炎などのリスクが低いと判断される高齢者の下顎埋伏智歯においても、多様な変化の可能性も念頭に置いた経過観察が肝要である。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02382&link_issn=&doc_id=20201221280014&doc_link_id=10.5843%2Fjsot.32.243&url=https%3A%2F%2Fdoi.org%2F10.5843%2Fjsot.32.243&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • 早期舌癌の術前DOI計測におけるCT、MRI、口腔内USの比較

    高村 真貴, 小林 太一, 新國 農, 勝良 剛詞, 山崎 学, 丸山 智, 田沼 順一, 林 孝文

    新潟歯学会雑誌   50 ( 2 )   107 - 107   2020年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 癌関連線維芽細胞と口腔扁平上皮癌細胞の相互作用におけるTGF-β/SOX9経路の役割

    羽賀 健太, 山崎 学, 丸山 智, 船山 昭典, 小林 正治, 田沼 順一

    Journal of Oral Biosciences Supplement   2020   329 - 329   2020年9月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • Kissing molars Class IIIの2例

    内藤 絵里子, 池田 順行, 勝見 祐二, 小山 貴寛, 高木 律男, 西山 秀昌, 林 孝文, 丸山 智, 山崎 学, 田沼 順一

    日本口腔科学会雑誌   69 ( 2 )   115 - 115   2020年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • Rac1-dependent phagocytosis of apoptotic cells by oral squamous cell carcinoma cells: A possible driving force for tumor progression. 査読 国際誌

    Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Masayuki Tsuneki, Hiroko Kato, Kenji Izumi, Jun-Ichi Tanuma, Jun Cheng, Takashi Saku

    Experimental cell research   112013 - 112013   2020年4月

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    記述言語:英語  

    Apoptotic cell death frequently occurs in human cancer tissues including oral squamous cell carcinoma (SCC), wherein apoptotic tumor cells are phagocytosed not only by macrophages but also by neighboring tumor cells. We previously reported that the engulfment of apoptotic SCC cells by neighboring SCC cells frequently occurs at the invading front. Therefore, we hypothesized that the phagocytosis of these apoptotic cells by tumor cells contributes to disease progression. Herein, using cultured oral SCC cells, we aimed to confirm whether tumor cells actually phagocytose apoptotic cells and to examine whether cellular activities are regulated by the phagocytosis of apoptotic cells. Co-culture experiments showed that living cells could ingest apoptotic cells into phagolysosomes. NSC23766, an inhibitor of Rac1, which is a key regulator of phagocytic cup formation in professional phagocytes, dramatically suppressed the phagocytosis of apoptotic cells by living cells. Additionally, cell migration and the secretion of DKK1, a tumor-promoting protein, were enhanced by co-culture with apoptotic cells, whereas NSC23766 inhibited these effects. These results show that tumor cells can actively phagocytose apoptotic neighbors in a Rac1-dependent manner and that such activity increases their migration. The regulation of apoptotic cell phagocytosis thus represents new directions for therapeutic intervention for oral cancer.

    DOI: 10.1016/j.yexcr.2020.112013

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  • がん細胞による死細胞貪食は細胞遊走とDKK1発現を促進する

    山崎 学, 丸山 智, 阿部 達也, 朔 敬, 田沼 順一

    日本病理学会会誌   109 ( 1 )   396 - 396   2020年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 舌上皮性異形成および上皮内癌と診断された病変の診断および治療の検討 査読

    新美 奏恵, 船山 昭典, 丸山 智, 勝良 剛詞, 新國 農, 田沼 順一, 林 孝文, 小林 正治

    日本口腔診断学会雑誌   33 ( 1 )   126 - 126   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • 下顎骨内に発生した類皮嚢胞の1例 査読

    笠原 映, 山崎 学, 丸山 智, 勝良 剛詞, 黒川 亮, 河原田 壮史, 林 孝文, 高木 律男, 田沼 順一

    日本口腔診断学会雑誌   33 ( 1 )   139 - 139   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • 舌腫瘍 査読

    河原田 壮史, 丸山 智, 笠原 映, 山崎 学, 林 孝文, 片桐 渉, 小林 正治, 田沼 順一

    日本口腔診断学会雑誌   33 ( 1 )   81 - 81   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • Low-grade myofibroblastic sarcoma of the tongue with difficulty of diagnosis: A case report and review of the literature 査読

    Masami Kawaharada, Wataru Katagiri, Satoshi Maruyama, Hideyoshi Nishiyama, Takafumi Hayashi, Tadaharu Kobayashi, Jun ichi Tanuma

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   33 ( 1 )   93 - 97   2020年

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    掲載種別:研究論文(学術雑誌)  

    © 2020 Asian AOMS(+) ASOMP(+) JSOP(+) JSOMS(+) JSOM(+) and JAMI We describe a case of low-grade myofibroblastic sarcoma (LGMS) on the dorsum of the tongue. A 41-year-old Japanese man noticed that a mass on the dorsal surface of the tongue had been present for 8 months. Computed tomography showed a homogeneously enhancing mass measuring 16 × 14 mm in the midline of the tongue. Magnetic resonance imaging showed a homogeneously enhancing mass with an almost clear margin on post-contrast T1-weighted imaging. The lesion was homogeneous with high signal intensity on T2-weighted imaging. The patient underwent excisional biopsy. Histologically, the tumor had an indistinct margin and was composed of spindle-shaped cells arranged in cellular fascicles. The cell nuclei showed signs of mild atypia. Positive staining for desmin and less strong staining for α-smooth muscle actin revealed that the tumor cells were myofibroblasts or smooth muscle cells. The tumor cells were negative for h-caldesmon. The MIB-1 labeling index of the tumor was 4.9 %. Thus, based on the histopathological, immunohistochemical and imaging findings, the tumor was finally diagnosed as LGMS. We reviewed the literature on the immunohistochemistry of LGMS. We suggest that immunohistochemistry is helpful in the differential diagnosis of LGMS.

    DOI: 10.1016/j.ajoms.2020.07.011

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  • 舌腫瘍 査読

    河原田 壮史, 丸山 智, 笠原 映, 山崎 学, 林 孝文, 片桐 渉, 小林 正治, 田沼 順一

    日本口腔内科学会雑誌   25 ( 2 )   71 - 71   2019年12月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔内科学会  

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  • PODXL1 promotes metastasis of the pancreatic ductal adenocarcinoma by activating the C5aR/C5a axis from the tumor microenvironment. 査読 国際誌

    Ken Saito, Hidekazu Iioka, Satoshi Maruyama, I Wayan Sumardika, Masakiyo Sakaguchi, Eisaku Kondo

    Neoplasia (New York, N.Y.)   21 ( 12 )   1121 - 1132   2019年12月

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    記述言語:英語  

    Pancreatic invasive ductal adenocarcinoma (PDAC) is a representative intractable malignancy under the current cancer therapies, and is considered a scirrhous carcinoma because it develops dense stroma. Both PODXL1, a member of CD34 family molecules, and C5aR, a critical cell motility inducer, have gained recent attention, as their expression was reported to correlate with poor prognosis for patients with diverse origins including PDAC; however, previous studies reported independently on their respective biological significance. Here we demonstrate that PODXL1 is essential for metastasis of PDAC cells through its specific interaction with C5aR. In vitro assay demonstrated that PODXL1 bound to C5aR, which stabilized C5aR protein and recruited it to cancer cell plasma membranes to receive C5a, an inflammatory chemoattractant factor. PODXL1 knockout in PDAC cells abrogated their metastatic property in vivo, emulating the liver metastatic mouse model treated with anti-C5a neutralizing antibody. In molecular studies, PODXL1 triggered EMT on PDAC cells in response to stimulation by C5a, corroborating PODXL1 involvement in PDAC cellular invasive properties via specific interaction with the C5aR/C5a axis. Confirming the molecular assays, histological examination showed coexpression of PODXL1 and C5aR at the invasive front of primary cancer nests as well as in liver metastatic foci of PDAC both in the mouse metastasis model and patient tissues. Hence, the novel direct interaction between PODXL1 and the C5aR/C5a axis may provide a better integrated understanding of PDAC biological characteristics including its tumor microenvironment factors.

    DOI: 10.1016/j.neo.2019.09.003

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  • 舌上皮性異形成および上皮内癌と診断された病変の診断および治療の検討

    新美 奏恵, 船山 昭典, 丸山 智, 勝良 剛詞, 新國 農, 田沼 順一, 林 孝文, 小林 正治

    日本口腔内科学会雑誌   25 ( 2 )   116 - 116   2019年12月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔内科学会  

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  • がん関連線維芽細胞は口腔扁平上皮癌においてSOX9発現を増強させ浸潤を促進する

    羽賀 健太, 山崎 学, 丸山 智, 鈴木 絢子, 干川 絵美, 船山 昭典, 三上 俊彦, 小林 正治, 泉 健次, 田沼 順一

    新潟歯学会雑誌   49 ( 2 )   86 - 86   2019年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 下顎第一大臼歯にみられたsubmerged toothの1例 対合歯である上顎第一大臼歯は低位を呈した1例

    鶴巻 浩, 渡部 桃子, 結城 龍太郎, 隅田 賢正, 山崎 学, 丸山 智

    新潟歯学会雑誌   49 ( 2 )   55 - 60   2019年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

    submerged toothは、一度萠出し咬合位にあった歯が、何らかの機序で低位となった状態であり、同様の病態はreimpaction、secondary retention等の名称で報告されている。乳歯においてはまれではないが、永久歯における報告は非常に少ない。今回、一度萠出し充填処置を施された下顎第一大臼歯が埋没し、対顎の上顎第一大臼歯は低位骨性癒着歯を呈したまれな1例を経験したのでその概要を報告した。症例は55歳の女性で、埋伏した下顎第一大臼歯の精査加療を目的に2017年11月に当科を紹介受診した。右側下顎第二大臼歯は著明に近心傾斜し、右側下顎第一大臼歯は口腔内に確認できなかった。また、右側上顎第一大臼歯は隣接歯に比し低位で、打診で高音を呈した。パノラマX線写真では右側下顎第一大臼歯は垂直位に埋伏し、歯冠部に修復物と考えられる不透過像を認めた。右側下顎第一大臼歯、第二大臼歯、右側上顎第一大臼歯は保存不能と判断し、全身麻酔下に抜歯術が施行された。下顎第一大臼歯は多量の歯石が沈着し、咬合面にはアマルガム充填がなされていた。病理組織学的所見では、下顎第一大臼歯は根分岐部でセメント質と象牙質が骨組織に置換され、骨性癒着と判断される像が認められた。また上顎第一大臼歯歯根には著明な吸収像が認められた。発生機序としては、上下の第一大臼歯が萠出中に何らかの原因で骨性癒着が生じ、周囲の成長とともに下顎第二大臼歯は近心傾斜し、咬合力を介して第一大臼歯の埋没が生じたと推察された。(著者抄録)

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  • Masseter muscle hypertrophy: A case report

    31 ( 6 )   428 - 431   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ajoms.2019.08.005

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  • 癌関連線維芽細胞はSOX9を高発現させ口腔癌細胞の遊走および浸潤を促進する(Cancer-associated fibroblasts promote the migration and invasion of oral cancer cells via enhancing SOX9 expression)

    羽賀 健太, 山崎 学, 丸山 智, 小林 正治, 田沼 順一

    日本癌学会総会記事   78回   P - 1258   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Cytoplasmic expression of SOX9 as a poor prognostic factor for oral squamous cell carcinoma. 査読 国際誌

    Yoshimasa Sumita, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Jun Cheng, Ritsuo Takagi, Jun-Ichi Tanuma

    Oncology reports   40 ( 5 )   2487 - 2496   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Transcription factor SRY‑box 9 (SOX9) is a key regulator of chondrocyte differentiation and sex determination, and it is also involved in the progression of various types of human cancer. However, its putative association with oral squamous cell carcinoma (OSCC) remains elusive. The aim of the present study was to investigate the expression profiles of SOX9 in various oral epithelial lesions, including OSCC. We performed immunohistochemical analysis of SOX9 expression in surgical specimens of OSCC, which simultaneously exhibited different grades of epithelial lesions, and analyzed the correlation between SOX9 expression and several clinicopathological factors. Moreover, we performed immunofluorescent staining, western blot analysis and real‑time reverse transcription‑polymerase chain reaction to assess SOX9 expression in OSCC HSC‑3 (a metastatic cell line) and HSC‑4 (a non‑metastatic cell line) cell lines. In surgical specimens, SOX9 expression was detected in the nuclei of proliferating cells in areas with epithelial dysplasia and carcinoma in situ, but not in areas with normal epithelia. Nuclear SOX9 expression was observed in most SCC cells. Notably, cytoplasmic SOX9 expression was confirmed only in some SCC cells; however, cytoplasmic SOX9 expression was significantly and positively correlated with poor clinical outcomes. Both protein and mRNA expression of SOX9 were significantly higher in the HSC‑3 cell line than that in the HSC‑4 line. Notably, however, only HSC‑3 cells exhibited cytoplasmic localization of SOX9 expression. Our findings indicate that SOX9 may be involved in the tumorigenesis and progression of OSCC. Furthermore, its cytoplasmic expression represents a potential predictive biomarker for tumor aggressiveness and OSCC prognosis.

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  • Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. 査読

    Takata K, Saito K, Maruyama S, Miyata-Takata T, Iioka H, Okuda S, Ling Y, Karube K, Miki Y, Maeda Y, Yoshino T, Steidl C, Kondo E

    Cancer science   110 ( 1 )   443 - 457   2018年11月

  • An unusual and difficult diagnosis of synovial chondromatosis: A case report. 査読

    Mikami Toshihiko, Kato Yusuke, Kojima Taku, Abe Tatsuya, Maruyama Satoshi, Nishiyama Hideyoshi, Hayashi Takafumi, Kobayashi Tadaharu

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   30 ( 5 )   422 - 427   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • 骨粗鬆症治療薬を中心とした薬剤関連顎骨壊死:病理診断の要点とその発生機序 査読

    丸山 智, 塚田真弓, 朔 敬

    病理と臨床   36 ( S )   134 - 138   2018年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Oral and maxillofacial manifestations of methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis: Report of a case 査読

    Kanae Niimi, Susumu Shingaki, Akinori Funayama, Toshihiko Mikami, Hideyoshi Nishiyama, Takafumi Hayashi, Manabu Yamazaki, Satoshi Maruyama, Takashi Saku, Takashi Saku, Tadaharu Kobayashi

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   31 ( 2 )   86 - 93   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © 2018 Asian AOMS(+) ASOMP(+) JSOP(+) JSOMS(+) JSOM(+) and JAMI Methotrexate (MTX) is a commonly used medicine treating rheumatoid arthritis (RA), and occasional patients receiving MTX are known to have lymphoproliferative disorders (MTX–LPDs). MTX–LPDs involving widely the maxillofacial region have been rarely documented, though those limited in the oral cavity are not so rare. We herein report a 63-year-old Japanese woman with RA, who had received MTX and developed maxillofacial lesions with lymph-node swelling as MTX–LPD. She had subcutaneous masses around her nasolabial sulcus in addition to a submucosal mass of the right side of the palate, which were similarly and homogeneously enhanced with contrastive media together with cervical, inguinal, and axillary lymph nodes in computed tomography. In biopsy, the palatal mass showed a nodular proliferation of CD20-positive large atypical lymphocytes without Epstein-Barr viral infection signals replacing the mucous gland, which resembled that seen in diffuse large B-cell lymphoma. Under the diagnosis of MTX–LPD, MTX was discontinued for four months, and those mass lesions and the swollen lymph nodes simultaneously disappeared. These findings suggest that observation after MTX withdrawal should be tried in the treatment of patients with MTX–LPD arising in the background of RA, even if the clinicopathological findings are suggestive of malignant lymphoma. This is a report describing comprehensive clinicopathological data of an oromaxillofacial MTX–LPD case with simultaneous lymphadenopathy.

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  • Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction. 査読 国際誌

    Ken Saito, Masakiyo Sakaguchi, Satoshi Maruyama, Hidekazu Iioka, Endy Widya Putranto, I Wayan Sumardika, Nahoko Tomonobu, Takashi Kawasaki, Keiichi Homma, Eisaku Kondo

    Journal of Cancer   9 ( 16 )   2916 - 2929   2018年

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    記述言語:英語  

    Pancreatic ductal adenocarcinoma (PDAC) is currently one of the most intractable malignancies with a typical scirrhous pattern in histology. Due to its abundant tumor stroma and scant vascularization, chemotherapeutic agents are considered inefficiently permeable to cancer nests, making it highly difficult to cure the patients with PDAC. However, PDAC is also considered to owe its intractability to other critical factors such as cellular interaction between tumor cells and tumor microenvironment as well as architectural barriers, which increases in therapeutic resistance. Here, we report a specific cellular interaction between PDAC cells and mesenchymal stem cells (MSCs) intermingled in PDAC stroma, which facilitates cancer invasion. Secretory phenotype profiling revealed that production of Amphiregulin (AREG) and MMP-3 were specifically upregulated under the coexistence of BxPC3 cells with human MSCs (approximately four to ten folds in AREG, and twenty to sixty-folds in MMP-3 compared to that of BxPC3 cells alone), whereas MMP-9 expression was decreased (less than one-tenth comparing with that of BxPC3 cells alone). Blockage of AREG production by its specific siRNA removed MSC-mediated driving force of BxPC3 invasiveness. Immunohistochemical analysis of tissue samples obtained both from PDAC patients and PDAC imitating mouse xenografted models revealed that significant coexpression of AREG and its receptor EGFR were detected on the cancer cells at invasive front. These results strongly suggested that cellular interaction between cancer cells and MSCs in the PDAC stroma might be critical to cancer progression, especially in the process of local invasion and the early stage development of metastasis.

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  • Clinical significance of intraoral strain elastography for diagnosing early stage tongue carcinoma: a preliminary study 査読

    Motoki Shingaki, Yutaka Nikkuni, Kouji Katsura, Nobuyuki Ikeda, Satoshi Maruyama, Ritsuo Takagi, Takafumi Hayashi

    ORAL RADIOLOGY   33 ( 3 )   204 - 211   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The aim of this study was to estimate the clinical significance of using intraoral strain elastography to establish an early diagnosis of tongue carcinoma.
    A total of 17 patients (11 men, 6 women; median age 67 years; age range 38-85 years) with a tumorous lesion of the tongue suggesting that early stage tongue carcinoma were enrolled in the study. Intraoral strain elastography was performed with a small hockey stick-shaped intraoperative probe and acoustic coupling polymer gel. The elasticity of the lesions was classified into four grades, with a score of 1 indicating a very soft tissue and a score of 4 indicating a very hard tissue. The patients were divided into two groups based on the histopathologically verified malignancy: carcinoma group (n = 15) and non-malignancy group (n = 2).
    All patients underwent surgical resection and histopathological examination of the surgical specimen. The pathology in the carcinoma group included 12 cases of squamous cell carcinoma and three cases of carcinoma in situ. The pathology in the non-malignancy group included one case of viral stomatitis and one case of pyogenic granuloma. The elasticity score was limited to 3 or 4 in the carcinoma group and 1 or 2 in the non-malignancy group. There was no significant difference in the elasticity scores between squamous cell carcinoma and carcinoma in situ.
    Although limited by the small number of subjects, the present results suggest that intraoral strain elastography could be an alternative noninvasive method for diagnosing tongue carcinoma.

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  • 口蓋腺に発生した小細胞癌の1例 査読

    小島 拓, 三上俊彦, 林 孝文, 丸山 智, 山崎 学, 小林正治

    日口腔外会誌   63 ( 7 )   358 - 363   2017年7月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

    <p>Small cell carcinoma (SmCC) arising in salivary gland is extremely rare, and most of the primary lesions occur in the parotid glands. We report a case of SmCC arising in the palatine gland in a 64-year-old man. The patient had an ulcerated tumor, measuring 35 × 20 mm, in the left side of the palate. A number of enlarged lymph nodes were recognized in the left cervical region. No distant metastases or other tumors were detected on <sup>18</sup>F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). A biopsy was performed from the palatal lesion, and the histopathological diagnosis was SmCC. The patient received radiotherapy alone, because chemotherapy had an increased risk of severe adverse events due to the presence of chronic kidney failure. Radiotherapy was administered to the left palatal and cervical regions in a total dose of 60 Gy. The tumor and the metastatic lymph nodes markedly shrank after the radiotherapy. However, 3 months later, metastatic cervical lymph nodes appeared in the right cervical region. Bony metastases to the right ilium and the left pubis were also detected on FDG-PET/CT. Additional radiotherapy was administered (60 Gy to the right cervical lymph nodes and 40 Gy to the metastatic bone lesions), but was not effective. Regrowth of the primary tumor and bilateral metastatic cervical lymph nodes appeared, and skin, lung, and liver metastases were identified. Finally, the patient died of multiple organ failure 12 months after the initial diagnosis.</p>

    DOI: 10.5794/jjoms.63.358

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  • Proteomic and histopathological characterization of the interface between oral squamous cell carcinoma invasion fronts and non-cancerous epithelia 査読

    Tatsuya Abe, Satoshi Maruyama, Manabu Yamazaki, Bo Xu, Hamzah Babkair, Yoshimasa Sumita, Jun Cheng, Tadashi Yamamoto, Takashi Saku

    EXPERIMENTAL AND MOLECULAR PATHOLOGY   102 ( 2 )   327 - 336   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Oral squamous cell carcinomas (SCCs) are frequently associated with pre-invasive lesions including carcinoma in-situ (CIS), and CISs further form lateral interfaces against surrounding normal or dysplastic epithelia (ND). At the interface where keratin (K) 17 positive (+) SCC/CIS cells are in contact with K13 + ND cells, "cell competition" must be evoked between two such different cell types. Thus, the aim of this study was to characterize the histopathology of the SCC/CIS-ND interface and to determine protein profiles around the interface by proteomics. A total of 112 lateral interfaces were collected from 55 CIS and 57 SCC foci, and they were investigated by immunohistochemistry and liquid chromatography-tandem mass spectrometry. The interfaces were morphologically classified into three types: vertical, oblique, and convex. There were several cellular changes characteristic to the interface, including apoptosis and hyaline bodies, which were more emphasized in SCC/CIS sides. The results suggested that ND cells were winners of cell competition against SCC/CIS cells. Then, the interfaces were divided into four vertical segments, and each segment was separately laser-microdissected from tissue sections with immunostaining for K13 or K17; the four segments included SCC/CIS away from(#1) or adjacent to (#2) the interface, and ND adjacent to (#3) or away from (#4) the interface. Proteome analyses revealed approximately 4000 proteins from SCC/CIS sides [#1 and #2] and 2800 proteins from ND sides [#3 and #4]. We quantitatively selected the top 25 proteins including ladinin-1 or interleukin-1 receptor antagonist protein, which were most contrastively increased or decreased in SCC/CIS or ND sides, respectively, and their specific immunohistochemical expression modes were confirmed in tissue sections as well as in cultured SCC cells. These molecules should be involved in the cellular crosstalk toward cell competition at the lateral interface of oral SCC/CIS and would be new candidates for histopathological distinction of oral malignancies. (C) 2017 Elsevier Inc. All rights reserved.

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  • Aberrant expression of the tight junction molecules claudin-1 and zonula occludens-1 mediates cell growth and invasion in oral squamous cell carcinoma 査読

    Hamzah Babkair, Manabu Yamazaki, Md. Shihab Uddin, Satoshi Maruyama, Tatsuya Abe, Ahmed Essa, Yoshimasa Sumita, Md. Shahidul Ahsan, Wael Swelam, Jun Cheng, Takashi Saku

    HUMAN PATHOLOGY   57   51 - 60   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    We reported that altered cell contact mediated by E-cadherin is an initial event in the pathogenesis of oral epithelial malignancies. To assess other effects of cell adhesion, we examined the expression levels of tight junction (TJ) molecules in oral carcinoma in situ (CIS) and squamous cell carcinoma (SCC). To identify changes in the expression of TJ molecules, we conducted an analysis of the immunohistochemical profiles of claudin-1 (CLDN-1) and zonula occludens-1 (ZO-1) in surgical specimens acquired from patients with oral SCC containing foci of epithelial dysplasia or from patients with CIS. We used immunofluorescence, Western blotting, reverse-transcription polymerase chain reaction, and RNA interference to evaluate the functions of CLDN-1 and ZO-1 in cultured oral SCC cells. TJ molecules were not detected in normal oral epithelial tissues but were expressed in SCC/CIS cells. ZO-1 was localized within the nucleus of proliferating cells. When CLDN-1 expression was inhibited by transfecting cells with specific small interference RNAs, SCC cells dissociated, and their ability to proliferate and invade Matrigel was inhibited. In contrast, although RNA interference mediated inhibition of ZO-1 expression did not affect cell morphology, it inhibited cell proliferation and invasiveness. Our findings indicated that the detection of TJ molecules in the oral epithelia may serve as a marker for the malignant phenotype of cells in which CLDN-1 regulates proliferation and invasion. (C) 2016 Elsevier Inc. All rights reserved.

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  • Tumour-associated macrophages are recruited and differentiated in the neoplastic stroma of oral squamous cell carcinoma 査読

    Ahmed Abdelaziz Mohamed Essa, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abe, Hamzah Babkair, Adel Mohamed Raghib, Eman Money El-Din Megahed, Jun Cheng, Takashi Sakui

    PATHOLOGY   48 ( 3 )   219 - 227   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    To confirm our hypothesis that macrophages recruited to fight against oral squamous cell carcinoma (SCC) invasion are functionally differentiated within neoplastic stromata, we analysed arrangements of macrophage subtypes and cancer-associated fibroblasts (CAFs) in their association with blood vasculatures in the neoplastic stroma. Surgical specimens of oral SCC were immunohistochemically examined for macrophage phenotypes (CD68, CD163, and CD204) and stromal environments (perlecan, connexin 43, and CD31). Human monocytes were co-cultured with ZK-1 cells of oral SCC origin in different culture conditions. SCC stromata were divided into two types: fascicular (fibroblast rich) and reticular (perlecan-rich). Regardless of stromal types, CD68 positive (+)/CD163+/CD204+ macrophages were recruited when blood vessels were abundant. Connexin 43+ fibroblasts were enriched in the fascicular stroma, where blood vessels were depleted. In co-culture experiments, monocytes, in the presence of ZK-1 cells, showed TNF-alpha(low)/IL-12(low) and IL-10(high)/VEGF(high)/MMP-9(high) with increased expression levels for fibronectin and perlecan. With direct contact with monocytes, SCC cells also expressed CD68 and CD163. SCC stromata were characterised by CD163+/CD204+ tumour-associated macrophages (TAMs) and connexin 43+ CAFs. TAMs are differentiated from monocytes by the physical contact with oral SCC cells in the perlecan-rich neoplastic stroma, which is also induced by the cross-talk between SCC cells and stromal cells including TAMs.

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  • Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa 査読

    Mayumi Hasegawa, Jun Cheng, Satoshi Maruyama, Manabu Yamazaki, Tatsuya Abe, Hamzah Babkair, Chikara Saito, Takashi Saku

    PATHOLOGY RESEARCH AND PRACTICE   212 ( 5 )   426 - 436   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER GMBH, URBAN & FISCHER VERLAG  

    The intercellular depdsit of perlecan, a basement-membrane type heparan sulfate proteoglycan, is considered to function as a growth factor reservoir and is enhanced in oral epithelial dysplasia and carcinoma in situ (CIS). However, it remains unknown which types of growth factors function in these perlecan-enriched epithelial conditions. The aim of this study was to determine immunohistochemically which growth factors were associated with perlecan in normal oral epithelia and in different epithelial lesions from dysplasia and CIS to squamous cell carcinoma (SCC). Eighty-one surgical tissue specimens of oral SCC containing different precancerous stages, along with ten of normal mucosa, were examined by immunohistochemistry for growth factors. In normal epithelia, perlecan and growth factors were not definitely expressed. In epithelial dysplasia, VEGF, SHH, KGF, Flt-1, and Flk-1 were localized in the lower half of rete ridges (in concordance with perlecan, 33-100%), in which Ki-67 positive cells were densely packed. In CIS, perlecan and those growth factors/receptors were more strongly expressed in the cell proliferating zone (63-100%). In SCC, perlecan and KGF disappeared from carcinoma cells but emerged in the stromal space (65-100%), while VEGF, SHH, and VEGF receptors remained positive in SCC cells (0%). Immunofluorescence showed that the four growth factors were shown to be produced by three oral SCC cell lines and that their signals were partially overlapped with perlecan signals. The results indicate that perlecan and its binding growth factors are differentially expressed and function in specific manners before (dysplasia/CIS) and after (SCC) invasion of dysplasia/carcinoma cells. (C) 2016 Elsevier GmbH. All rights reserved.

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  • Simultaneous immunolocalization of desmoglein 3 and IgG4 in oral pemphigus vulgaris: IgG4 predominant autoantibodies in its pathogenesis 査読

    Tatsuya Abe, Satoshi Maruyama, Hamzah Babkair, Manabu Yamazaki, Jun Cheng, Takashi Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   44 ( 10 )   850 - 856   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    BackgroundOral pemphigus vulgaris (PV), an autoimmune blistering disease, is mainly mediated by autoantibodies against desmoglein (Dsg) 3. However, no attention has been paid to IgG subclasses of the autoantibodies against Dsg3 in the diagnostic procedure for PV. Thus, our aim in this study was to investigate whether Dsg3 and any of IgG subclasses are immunohistochemically colocalized in tissue sections of PV oral mucosa.
    Materials and MethodsSerial sections cut from formalin-fixed paraffin blocks of biopsy specimens of 9 PV cases and those of normal buccal mucosa surgically removed for fibro-epithelial polyps were comparatively examined for immunohistochemical localizations for Dsg3, IgG4, and IgG.
    ResultsDsg3 was demonstrated in a dot-like pattern on the cell border and in the cytoplasm of the whole epithelial layer in both normal and PV specimens, while its staining was irregular among floating epithelial sheets of PV. IgG4 was also demonstrated in a punctuated fashion on the cell border among floating epithelial sheets, which was nearly identical to the immunohistochemical profile of Dsg3. In addition to being detected in the epithelial part, IgG4 signals were prominently localized in plasma cells scattered in the granulation tissue, where ratios of IgG4-positive (+) plasma cells to IgG+ cells were extraordinarily higher (mean 28%) than those in normal mucosa.
    DiscussionThese findings confirmed for the first time that autoantibodies against Dsg3 are mainly composed of IgG4 in oral PV and that the combined immunohistochemistry for Dsg3 and IgG4 can be a valuable aid in confirming a histopathological diagnosis of PV.

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  • Paradental cyst is an inclusion cyst of the junctional/sulcular epithelium of the gingiva: histopathologic and immunohistochemical confirmation for its pathogenesis 査読

    Satoshi Maruyama, Manabu Yamazaki, Tatsuya Abe, Hamzah Babkair, Jun Cheng, Takashi Saku

    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY   120 ( 2 )   227 - 237   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Objective. The aim of this study was to characterize the histologic and immunohistochemical profiles of paradental cystlining epithelia to clarify its histopathogenesis.
    Study Design. Ten surgical specimens of paradental cysts were examined for clinical profiles and to determine the histopathologic characteristics of the lining epithelia. Immunohistochemical profiles for keratin (K) subtypes, as well as for perlecan, UEA-I lectin binding, and proliferating cell nuclear antigen (PCNA), were determined and compared.
    Results. The paradental cyst was clinically characterized by its occurrence in young adults (mean age, 36.8 years; male, 42.8, female 27.8). Eight of the 10 cases arose in the retromolar area. The cyst wall was basically granulation tissue that was attached to the periodontal ligament space. Thin irregular anastomosing epithelial cords lined the cyst walls of immature granulation tissue with vascular dilation and hemorrhage. The intercellular space of the lining epithelia was widened with inflammatory cell infiltrates. Immunohistochemically, the lining was positive for K13, K14, K17, K19, UEA-I binding, and perlecan, suggesting its junctional/sulcular epithelial character.
    Conclusion. The results showed that the paradental cyst was lined by epithelial cells with characteristics of the junctional/sulcular epithelium. The cyst can thus be considered as a kind of inclusion cyst arising in the periodontal pocket, most frequently of the mandibular third molars of young adults.

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  • 歯周炎罹患歯肉組織におけるNeprilysin(Alzheimer病関連遺伝子)の発現

    根津 新, 久保田 健彦, 丸山 智, 水田 昌毅, 堀水 慎, 濃野 要, 保苅 崇大, 両角 俊哉, 朔 敬, 吉江 弘正

    日本歯周病学会会誌   57 ( 秋季特別 )   131 - 131   2015年8月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯周病学会  

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  • Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells 査読

    Kamal Al-Eryani, Jun Cheng, Tatsuya Abe, Satoshi Maruyama, Manabu Yamazaki, Hamzah Babkair, Ahmed Essa, Takashi Saku

    HUMAN PATHOLOGY   46 ( 7 )   991 - 999   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Based on our previous finding that protease-activated receptor 2 (PAR-2) regulates hemophagocytosis of oral squamous cell carcinoma (SCC) cells, which induces their heme oxygenase 1- dependent keratinization, we have formulated a hypothesis that PAR-2 functions in wider activities of SCC cells. To confirm this hypothesis, we investigated immunohistochemical profiles of PAR-2 in oral SCC tissues and its functional roles in cell proliferation and invasion in SCC cells in culture. The PAR-2 expression modes were determined in 48 surgical tissue specimens of oral SCC. Using oral SCC derived cell systems, we determined both gene and protein expression levels of PAR-2. SCC cell proliferation and invasive properties were also examined in conditions in which PAR-2 was activated by the synthetic peptide SLIGRL. PAR-2 was immunolocalized in oral SCC and carcinoma in situ cells, especially in those on the periphery of carcinoma cell foci (100% of cases), but not in normal oral epithelia. Its expression at both gene and protein levels was confirmed in 3 oral SCC cell lines including ZK-1. Activation of PAR-2 induced ZK-1 cell proliferation in a dose-dependent manner. PAR-2 activated ZK-1 cells invaded faster than nonactivated ones. The expression of PAR-2 is specific to oral malignancies, and PAR-2 regulates the growth and invasion of oral SCC cells. (C) 2015 Elsevier Inc. All rights reserved.

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  • Keratin 17 is co-expressed with 14-3-3 sigma in oral carcinoma in situ and squamous cell carcinoma and modulates cell proliferation and size but not cell migration 査読

    Toshihiko Mikami, Satoshi Maruyama, Tatsuya Abe, Takanori Kobayashi, Manabu Yamazaki, Akinori Funayama, Susumu Shingaki, Tadaharu Kobayashi, Cheng Jun, Takashi Saku

    VIRCHOWS ARCHIV   466 ( 5 )   559 - 569   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Expression of keratin (K) 13 is replaced with that of K17 when squamous cells of the oral mucosa transform from normal and dysplastic epithelia to carcinoma in situ (CIS) and squamous cell carcinoma (SCC). Since 14-3-3 sigma is functionally associated with K17, we examined possible relationships between expression of K17 and 14-3-3 sigma in oral CIS and SCC tissues by immunohistochemistry. We furthermore examined whether or not K17 expression or knockdown by small interfering RNA (siRNA) modulates the behavior of SCC cells in culture in terms of cell proliferation and migration. In tissue specimens of oral SCC and CIS, the pattern of cytoplasmic expression of 14-3-3 sigma and K17 was similar but neither was expressed in normal or dysplastic epithelia. Both proteins were demonstrated in the cytoplasm of control oral SCC ZK-1 cells, but expression of 14-3-3 sigma changed from cytoplasmic to nuclear upon knockdown of K17. In carcinoma cells, therefore, cytoplasmic localization of 14-3-3 sigma seems to accompany expression of K17. In K17-knockdown cells, proliferation was significantly suppressed at 4 days after seeding. In addition, the cell size of K17-knockdown cells was significantly smaller than that of control cells; as a result of which in the migration experiments, we found delayed closure of scratch wounds but migration as such was not affected. We conclude that K17 expression promotes SCC cell growth and cell size but does not affect cell migration. K17 expression is accompanied by cytoplasmic expression of 14-3-3 sigma, indicative of their functional relationship.

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  • Keratin pearl degradation in oral squamous cell carcinoma: reciprocal roles of neutrophils and macrophages 査読

    Ahmed A. M. Essa, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abe, Hamzah Babkair, Jun Cheng, Takashi Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   43 ( 10 )   778 - 784   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    BackgroundWe have reported that neutrophilic infiltration was associated with round-shaped dyskeratosis foci, a kind of keratin pearl, of oral carcinoma in situ and that those inflammatory cells are recruited from intra-epithelially entrapped blood vessels. Based on these lines of evidence, we have formulated a hypothesis that keratin pearls are terminally degraded by neutrophils. To confirm this hypothesis, we investigated immunohistochemically stepwise degradation of keratin pearls in oral squamous cell carcinoma (SCC) to clarify any other type scavenger cells in addition to neutrophils are involved in this particular degradation process.
    MethodsNeutrophils (neutrophil elastase) and macrophage subpopulations (CD68, CD163 and CD204) were immunohistochemically localized in 30 cases of oral SCC with typical round-shaped keratin pearls. SCC cells were revealed by immunohistochemistry for keratin (K) 17, and blood vessels were demonstrated by CD31.
    ResultsKeratin pearl degradation process was divided into four steps: (i) intact stage: no macrophage infiltration but minimal neutrophils were found in keratin pearls; (ii) neutrophil recruit stage: no macrophage infiltration but focal neutrophilic infiltration within the pearls; (iii) neutrophil predominant stage: dense neutrophil infiltration with minimal macrophages and segregated keratinized cancer cells strongly positive for K17; and (iv) macrophage predominant stage: dense infiltration of CD68-, CD163 (mononuclear)- and CD204 (multinucleated)-positive macrophages engulfing detached keratinized SCC cells.
    ConclusionKeratin pearl degradation in oral SCC is strictly regulated by two types of scavenger cells: neutrophils, which perform initial tasks, and macrophages, which reciprocally take over from neutrophils the role to finalize the degradation processes.

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  • MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells 査読

    Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abe, Ahmed Essa, Hamzah Babkair, Jun Cheng, Takashi Saku

    LABORATORY INVESTIGATION   94 ( 11 )   1260 - 1272   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8) is a secreted glycoprotein that promotes clearance of apoptotic cells by bridging phosphatidylserine on apoptotic cells and integrin alpha beta 3/5 on phagocytes. High expression of MFG-E8 has been reported in various types of cancer in humans. Apoptotic figures are frequently found in the surgical samples of oral squamous cell carcinoma (SCC) and carcinoma in situ, and we have often observed apoptotic carcinoma cells engulfed by macrophages or even by neighboring carcinoma cells. Thus we hypothesized that MFG-E8 might promote engulfment of apoptotic carcinoma cells by living carcinoma cells and that MFG-E8 expressed by carcinoma cells could contribute to tumor progression. The aim of this study was to elucidate the biological role of MFG-E8 in oral SCC. Fifty-three surgical specimens of oral SCC were used for immunohistochemistry for MFG-E8, and the expression profiles were correlated with clinicopathological properties. Also, we examined the MFG-E8 expression patterns and functions using three human oral SCC cell lines. Most of the cases had MFG-E8-positive SCC cells, and the expression of MFG-E8 was correlated with such clinicopathological features as tumor size, pathological stage, locoregional recurrence, scattering invasion pattern, and SCC cell figures engulfing apoptotic SCC cells. The MFG-E8 staining was enhanced in apoptotic SCC cells, some of which were apparently engulfed by the neighboring SCC cells. ZK-1 cells showed high MFG-E8 expression, and its localization was found in the cytoplasm and the cell surface. Transient MFG-E8 knockdown by siRNA in ZK-1 decreased cell proliferation and invasiveness and increased cell death. Thus we have demonstrated that MFG-E8 promotes tumor progression in oral SCC and that it might be involved in the clearance of apoptotic SCC cells by living SCC cells.

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  • Perlecan-enriched intercellular space of junctional epithelium provides primary infrastructure for leukocyte migration through squamous epithelial cells 査読

    Satoshi Maruyama, Manami Itagaki, Hiroko Ida-Yonemochi, Takehiko Kubota, Manabu Yamazaki, Tatsuya Abe, Hiromasa Yoshie, Jun Cheng, Takashi Saku

    HISTOCHEMISTRY AND CELL BIOLOGY   142 ( 3 )   297 - 305   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The aim of this study was to demonstrate the presence of intraepithelial stroma represented by extracellular matrix (ECM) deposits in the junctional epithelium to clarify its function as a scaffold for leukocyte migration through epithelial cells. Twenty-three biopsy specimens from the gingiva including the junctional epithelium were examined to determine comparative protein and gene level expression profiles for keratin and ECM molecules between the junctional epithelium and the gingival epithelium using immunohistochemistry and in situ hybridization. Intraepithelial leukocyte types and frequencies were also determined and compared between the junctional and gingival epithelia. In the junctional epithelium, which was positive for keratin 19, perlecan was strongly deposited in intercellular space of the whole epithelial layer, while it was faintly positive around the parabasal layer of the gingival epithelium. Perlecan mRNA signals were enhanced to a greater degree in both epithelial and inflammatory cells within the junctional epithelium. In the junctional epithelium, greater numbers of neutrophils and macrophages were found as compared with the gingival epithelium. Our results showed that perlecan is the primary ECM molecule comprising intraepithelial stroma of the junctional epithelium, in which leukocytes may migrate on ECM scaffolds in intercellular space toward the surface of the gingival sulci or pockets.

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  • Three-dimensional visualization of perlecan-rich neoplastic stroma induced concurrently with the invasion of oral squamous cell carcinoma 査読

    Satoshi Maruyama, Yoshihito Shimazu, Tomoo Kudo, Kaori Sato, Manabu Yamazaki, Tatsuya Abe, Hamzah Babkair, Jun Cheng, Takaaki Aoba, Takashi Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   43 ( 8 )   627 - 636   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    BACKGROUND: We have demonstrated the induction of perlecan-rich stroma of oral squamous cell carcinoma (SCC) on and after its start of invasion. However, it remains unknown how such a neoplastic stroma is actually arranged in tumor tissues.
    METHODS: To this end, tissue microarray samples, in which keratin and perlecan were contrastively labeled by immunohistochemistry, were three-dimensionally analyzed using digital images and image analysis software to demonstrate the relationship between SCC foci and the perlecan-positive stromal space or that between carcinoma in situ (CIS) and invasive SCC foci.
    RESULTS: The three-dimensional (3D) reconstruction demonstrated three kinds of perlecan profiles for inside (I) and outside (O) areas of the carcinoma cell focus: mode 1, 1(+)/O-; mode 2, 1(+)/O+; and mode 3, 1(-)/O+. Mode 1 was seen in CIS as well as SCC tumor massifs in the surface part. Mode 2 was seen in small SCC foci, which seemed isolated in 2D sections but were mostly continuous with the tumor massif in 3D reconstructions. Mode 3 was limited to small SCC foci, which were truly segregated from the tumor massif.
    CONCLUSIONS: The results indicated that the 2D SCC focus isolation could not be regarded as invasion but that the SCC foci surrounded by perlecan-positive stroma (modes 2 and 3) could be regarded as a more objective measure for invasion of SCC. This is the first 3D tissue-level demonstration of the neoplastic stroma space induced with oral SCC invasion, the presence of which we have predicted based on our previous 2D and tissue culture evidence.

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  • 口腔扁平上皮癌とその境界病変における術中迅速病理診断の意義 局所再発に関する臨床病理学的検討

    御代田 駿, 小林 孝憲, 宮島 久, 永田 昌毅, 星名 秀行, 小林 正治, 高木 律男, 丸山 智, 朔 敬

    日本口腔科学会雑誌   63 ( 4 )   447 - 447   2014年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • Hybrid ameloblastoma and adenomatoid odontogenic tumor: report of a case and review of hybrid variations in the literature 査読

    Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abe, Hamzah Babkair, Hajime Fujita, Ritsuo Takagi, Jun-ichi Koyama, Takafumi Hayashi, Jun Cheng, Takashi Saku

    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY   118 ( 1 )   E12 - E18   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Hybrid odontogenic tumors including 2 or more different histologic types have been documented, but their occurrences are not very common. We present a case of hybrid odontogenic tumor composed of ameloblastoma and adenomatoid odontogenic tumor (AOT) arising in the mandibular molar region of a 31-year-old Japanese woman who had a history of familial adenomatous polyposis. The tumor, measuring 10 mm in diameter, was surgically removed from the alveolar bone. Histopathologically, the tumor consisted of both follicular and plexiform types of ameloblastoma in which multiple and smaller foci of AOT were intermingled. There have been 3 reported cases of hybrid ameloblastoma and AOT, all of which presented unicystic types as ameloblastoma components. This, however, is the first report of a hybrid tumor containing an authentic solid-type ameloblastoma compartment and an AOT compartment in a patient with a background of familial adenomatous polyposis.

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  • 口腔扁平上皮癌とその境界病変における術中迅速病理診断の意義 再発に関する臨床病理学的検討

    御代田 駿, 小林 孝憲, 宮島 久, 小林 正治, 高木 律男, 丸山 智, 朔 敬

    新潟医学会雑誌   128 ( 3 )   143 - 143   2014年3月

  • 悪性腫瘍 口腔粘膜扁平上皮癌および悪性境界病変の再発に関する臨床病理学的検討

    御代田 駿, 小林 孝憲, 宮島 久, 星名 秀行, 小林 正治, 高木 律男, 丸山 智, 朔 敬

    日本口腔診断学会雑誌   27 ( 1 )   122 - 122   2014年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • Intramuscular keratocyst as a soft tissue counterpart of keratocystic odontogenic tumor: differential diagnosis by immunohistochemistry 査読

    Tatsuya Abe, Satoshi Maruyama, Manabu Yamazaki, Ahmed Essa, Hamzah Babkair, Toshihiko Mikami, Susumu Shingaki, Tadaharu Kobayashi, Takafumi Hayashi, Jun Cheng, Takashi Saku

    HUMAN PATHOLOGY   45 ( 1 )   110 - 118   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Keratocystic odontogenic tumor (KCOT), a developmental jaw cyst previously referred to as odontogenic keratocyst (OKC), typically arises in the jawbone. In this article, however, we report a case of KCOT located within the temporalis muscle. We compared its immunohistochemical profiles with those of authentic jaw KCOT, orthokeratinized odontogenic cyst, and epidermoid cyst in order to consider whether a soft tissue counterpart of KCOT could be a separate disease entity. The patient was a 46-year-old man with a well-defined cystic lesion within the left temporalis muscle. On computed tomographic images, the lesion was recognized as a cystic lesion, although KCOT was not included in, the clinical differential diagnoses. The location of the lesion was not within bone but, rather; within the temporalis muscle that was attached to the jawbones. Our review of the literature has disclosed more than 20 peripheral KCOT cases of the oral mucosa and more than 10 cases of the skin, but only 1 case, arising in muscle. Immunohistochemical investigation of the present intramuscular case reveals KCOT-characteristic profiles distinct from the other 3 types of cysts investigated. The results indicate that KCOT-like lesions can arise within soft tissues, although use of the term odontogenic might seem inappropriate in those cases. (C) 2014 Elsevier Inc. All rights reserved.

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  • Radiation-induced undifferentiated high-grade pleomorphic sarcoma (malignant fibrous histiocytoma) of the mandible: Report of a case arising in the background of long-standing osteomyelitis with a review of the literature 査読

    Takahiro Koyama, Takanori Kobayashi, Satoshi Maruyama, Tatsuya Abe, Wael Mohamed Swelam, Yasumitu Kodama, Hideyuki Hoshina, Ritsuo Takagi, Takafumi Hayashi, Takashi Saku

    PATHOLOGY RESEARCH AND PRACTICE   210 ( 12 )   1123 - 1129   2014年

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    記述言語:英語   出版者・発行元:ELSEVIER GMBH, URBAN & FISCHER VERLAG  

    We report a rare case of radiation-induced undifferentiated high-grade pleomorphic sarcoma (UPS) (malignant fibrous histiocytoma, MFH) in the right mandible of a 44-year-old woman. The patient had suffered from osteomyelitis of the same region of the mandible for several years, which was considered to be due to radiotherapy for a malignant lymphoma in her right neck 19 years before. The tumor appeared as an exophytic and invasive growth in the molar region of the mandible. Histopathologically, the tumor consisted of an interlacing proliferation of vimentin-immunopositive spindle-shaped fibroblastic cells with bizarre nuclei with high Ki-67 labeling scores, and tumor cells showed storiform patterns mixed with pleomorphic cells. Taking the history of radiation into consideration, we diagnosed the lesion as radiation-induced MFH/UPS. Including the present case, there have been only 14 documented cases of radiation-induced UPS in the jawbone, and this is the first UPS case arising in the follow-up period of long-standing osteomyelitis. (C) 2014 Elsevier GmbH. All rights reserved.

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  • 悪性腫瘍 口腔粘膜扁平上皮癌および悪性境界病変の再発に関する臨床病理学的検討

    御代田 駿, 小林 孝憲, 宮島 久, 星名 秀行, 小林 正治, 高木 律男, 丸山 智, 朔 敬

    日本口腔内科学会雑誌   19 ( 2 )   121 - 121   2013年12月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔内科学会  

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  • Hemophagocytosis-mediated keratinization in oral carcinoma in situ and squamous cell carcinoma: A possible histopathogenesis of keratin pearls 査読

    Kamal Al-Eryani, Jun Cheng, Tatsuya Abe, Manabu Yamazaki, Satoshi Maruyama, Masayuki Tsuneki, Ahmed Essa, Hamzah Babkair, Takashi Saku

    JOURNAL OF CELLULAR PHYSIOLOGY   228 ( 10 )   1977 - 1988   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Although the histopathogenetic process of keratin pearls is still poorly understood, acceleration of keratinization in squamous cell carcinoma (SCC) cells may represent one possible therapeutic avenue. Based on our histopathological observations, we have hypothesized that SCC cells are keratinized by phagocytosis of extravasated erythrocytes. To confirm this hypothesis, we firstly examined immature keratin pearls in oral carcinoma in situ (CIS) and mature ones in SCC by immunohistochemistry. Concentric dyskeratotic cells in CIS keratin pearls became positive for keratin (K) 10, K17, heme oxygenase-1 (HO-1), or protease activated receptor-2 (PAR-2), a candidate regulator for hemophagocytosis. When ZK-1 cells, an SCC cell system, were incubated with human peripheral blood erythrocytes, or with crude and purified hemoglobins (Hbs), their erythro-hemophagocytotic activities were confirmed by immunofluorescence. Immunofluorescence signals for K10, K17, and HO-1 were enhanced due to hemophagocytosis in time-dependent manners. mRNA expression levels for the three molecules were most enhanced by purified Hb, followed by crude Hb and erythrocytes. K17/K10 mRNA expression levels were more elevated when PAR-2 was activated in ZK-1 cells. The results indicated that immature and mature keratin pearls in CIS and SCC were generated by oxidative stresses derived from erythro-hemophagocytosis, which might mediate HO-1 expression and be regulated by PAR-2. Thus, hemorrhage from the rupture of blood vessels can be one of the triggers for keratin pearl formation in oral CIS and SCC. J. Cell. Physiol. 228: 1977-1988, 2013. (c) 2013 Wiley Periodicals, Inc.

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  • Identification of the actinomycete 16S ribosomal RNA gene by polymerase chain reaction in oral inflammatory lesions 査読

    Kayo Kuyama, Kenji Fukui, Eriko Ochiai, Satoshi Maruyama, Kimiharu Iwadate, Takashi Saku, Hirotsugu Yamamoto

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   116 ( 4 )   485 - 491   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives To examine the histopathological characteristics of inflammatory lesions containing Actinomyces based on DNA sequencing. Furthermore, case reports of actinomycosis in the maxillofacial region are summarized by a review of the literature. Study design The study comprised 12 cases of inflammatory lesions containing Actinomyces as diagnosed by DNA analysis. The average age of the subjects was 59 ± 15 years (6 males
    6 females). Results The distribution of causative bacteria was: Actinomyces israelii in 9 cases, Actinomyces gerencseriae in 2 cases, and Actinomyces naeslundii in 1 case. Four cases diagnosed by DNA sequencing were positive for "Druse," a known morphological diagnostic characteristic of actinomycosis, and 8 cases lacked typical colony formation. Conclusions DNA analysis using paraffin-embedded samples is effective for both early and accurate diagnosis of oral lesions containing Actinomyces. © 2013 Elsevier Inc. All rights reserved.

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  • Gene and protein localisation of tumour necrosis factor (TNF)-α converting enzyme in gingival tissues from periodontitis patients with drug-induced gingival overgrowth. 査読

    Tomita T, Kubota T, Nakasone N, Morozumi T, Abe D, Maruyama S, Shimizu T, Horimizu M, Saku T, Yoshie H

    Archives of oral biology   58 ( 8 )   1014 - 1020   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma 査読

    Masayuki Tsuneki, Manabu Yamazaki, Satoshi Maruyama, Jun Cheng, Takashi Saku

    LABORATORY INVESTIGATION   93 ( 8 )   921 - 932   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Podoplanin (PDPN), one of the representative mucin-like type-I transmembrane glycoproteins specific to lymphatic endothelial cells, is expressed in various cancers including squamous cell carcinoma (SCC). On the basis of our previous studies, we have developed the hypothesis that PDPN functions in association with the extracellular matrix (ECM) from the cell surface side. The aim of this study was to elucidate the molecular role of PDPN in terms of cell adhesion, proliferation, and migration in oral SCC cells. Forty-four surgical specimens of oral SCC were used for immunohistochemistry for PDPN, and the expression profiles were correlated with their clinicopathological properties. Using ZK-1, a human oral SCC cell system, and five other cell systems, we examined PDPN expression levels by immunofluorescence, western blotting, and real-time PCR. The effects of transient PDPN knockdown by siRNA in ZK-1 were determined for cellular functions in terms of cell proliferation, adhesion, migration, and invasion in association with CD44 and hyaluronan. Cases without PDPN-positive cells were histopathologically classified as less-differentiated SCC, and SCC cells without PDPN more frequently invaded lymphatics. Adhesive properties of ZK-1 were significantly inhibited by siRNA, and PDPN was shown to collaborate with CD44 in cell adhesion to tether SCC cells with hyaluronan-rich ECM of the narrow intercellular space as well as with the stromal ECM. There was no siRNA effect in migration. We have demonstrated the primary function of PDPN in cell adhesion to ECM, which is to secondarily promote oral SCC cell proliferation.

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  • Central neurofibroma of the mandible: Report of a case and review of the literature 査読

    Hamdy Metwaly, Jun Cheng, Satoshi Maruyama, Manabu Yamazaki, Ahmed Essa, Tatsuya Abé, Hamzah Babkair, Hideyuki Hoshina, Ritsuo Takagi, Takafumi Hayashi, Takashi Saku

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   25 ( 3 )   294 - 298   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A case of solitary central neurofibroma of the mandible arising in a 70-year-old man is reported. The patient had a radiolucent lesion, measuring 16. mm in diameter, with central radiopaque freckles in the right incisor-canine region of the mandible, which was discovered incidentally during routine dental check-up. The lesion was persisted for 10 years without any symptoms or complication. It was clinically diagnosed as benign tumor and surgically removed under general anesthesia. Histologically, the removed tumor was relatively well demarcated and composed of a sparse proliferation of elongated spindle-shaped cells with wavy nuclei in loosely textured connective tissue stroma, which was associated with bone formation. Clinicopathological features of central neurofibroma of the jaw bone are reviewed from the literature. This is the first report of central neurofibroma arising in the anterior part of the mandible. © 2012 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI.

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  • Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells 査読

    Masayuki Tsuneki, Satoshi Maruyama, Manabu Yamazaki, Bo Xu, Ahmed Essa, Tatsuya Abé, Hamzah Babkair, Jun Cheng, Tadashi Yamamoto, Takashi Saku

    Biochemical and Biophysical Research Communications   434 ( 1 )   124 - 130   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In previous studies, we have shown several lines of evidence that podoplanin (PDPN) plays an important role in cell adhesion via its association with extracellular components in neoplastic conditions, though there has been no trial to search for PDPN-interaction molecules in the extracellular milieu. To screen for those molecules, we performed proteomics-based analysis using liquid chromatography-tandem mass spectrometry followed by co-immunoprecipitation for PDPN in ZK-1, an oral squamous cell carcinoma (SCC) cell system whose cell membrane molecules were cross-linked with each other in their extracellular compartments, and we identified heat shock protein (HSP) A9 as one of the extracellular PDPN bound molecules. Effects of transient PDPN knockdown by siRNA in ZK-1 were also comparatively examined for cellular behaviors in terms of HSPA9 expression and secretion. Finally, HSPA9 expression modes were immunohistochemically visualized in oral SCC tissue specimens. HSPA9 was secreted from ZK-1 cells, and the expression and secretion levels of HSPA9 gene and protein were well coordinated with those of PDPN. Immunohistochemically, HSPA9 and PDPN were co-localized in ZK-1 cells and oral SCC foci, especially in the peripheral zone. In conclusion, the results indicate that HSPA9 secreted by oral SCC cells interacts with PDPN on their cell surface in an autocrine manner and regulates their growth and invasiveness. © 2013 Elsevier Inc.

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  • Podoplanin is a novel myoepithelial cell marker in pleomorphic adenoma and other salivary gland tumors with myoepithelial differentiation 査読

    Masayuki Tsuneki, Satoshi Maruyama, Manabu Yamazaki, Ahmed Essa, Tatsuya Abe, Hamzah Ali Babkair, Md Shahidul Ahsan, Jun Cheng, Takashi Saku

    VIRCHOWS ARCHIV   462 ( 3 )   297 - 305   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The expression of podoplanin, one of the representative immunohistochemical markers for lymphatic endothelium, is upregulated in various kinds of cancers. Based on our previous studies, we have developed a hypothesis that podoplanin plays a role in cell adhesion via its association with extracellular matrix (ECM). Since salivary pleomorphic adenoma is histologically characterized by its ECM-enriched stroma, we firstly wanted to explore the expression modes of podoplanin in pleomorphic adenoma and related salivary tumors by immunohistochemistry. In normal salivary gland, podoplanin was specifically localized in myoepithelial cells, which were also positively labeled by antibodies against P63, of the intercalated duct as well as acini. In pleomorphic adenoma, podoplanin was colocalized with P63 and CD44 in basal cells of glandular structures as well as in stellate/spindle cells in myxochondroid matrices, where perlecan and hyaluronic acid were enriched. The expression of podoplanin was confirmed at both protein and mRNA levels in pleomorphic adenoma cell systems (SM-AP1 and SM-AP4) by using immunofluorescence, western blotting, and reverse transcription polymerase chain reaction. Podoplanin was localized on the cell border as well as in the external periphery of the cells. Moreover, podoplanin expression was also confirmed in tumor cells with myoepithelial differentiation in myoepithelioma and intraductal papilloma. The results indicate that podoplanin can be regarded as a novel myoepithelial marker in salivary gland tumors and suggest that podoplanin's communication with ECM molecules is essential to phenotypic differentiation to myoepithelial cells.

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  • Keratin 10-positive orthokeratotic dysplasia: a new leucoplakia-type precancerous entity of the oral mucosa 査読

    Takanori Kobayashi, Satoshi Maruyama, Tatsuya Abe, Jun Cheng, Ritsuo Takagi, Chikara Saito, Takashi Saku

    HISTOPATHOLOGY   61 ( 5 )   910 - 920   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Aims: We investigated a group of oral mucosal lesions with characteristic hyperorthokeratotic foci, which we termed orthokeratotic dysplasia (OKD), to determine if it could be identified as a distinct histopathological entity.
    Methods and results: We screened 282 surgical specimens from 200 patients with oral leucoplakia-type squamous cell carcinoma (SCC) or carcinoma in situ (CIS). OKD was defined as an oral mucosal lesional focus in which hyperorthokeratosis was predominant in the presence of the granular cell layer. A total of 84 OKD foci from 62 cases found among the 200 SCC/CIS cases were analysed. According to its rete ridge shapes, OKD was classified into three subtypes: flat (14.3%), leg (63.1%) and intermediate (22.6%). Eighty per cent of OKD foci were adjacent to the main foci of SCC or CIS, and they were demarcated sharply from each other. Most of the OKD constituent cells were immunopositive for keratin 10, but not for keratins 13, 17 or 19. Numbers of Ki-67-positive cells in the first basal layer were greater in OKD than in normal epithelia.
    Conclusions: The findings indicate that OKD is a distinct variant of epithelial dysplasia related to malignancies, and hence that it is important to recognize its existence.

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  • Parenchymal-stromal switching for extracellular matrix production on invasion of oral squamous cell carcinoma 査読

    Hamdy Metwaly, Satoshi Maruyama, Manabu Yamazaki, Masayuki Tsuneki, Tatsuya Abe, Kai Yu Jen, Jun Cheng, Takashi Saku

    HUMAN PATHOLOGY   43 ( 11 )   1973 - 1981   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    It is poorly understood which cell type, tumor cells, or stromal cells are responsible for the production of extracellular matrix molecules in the neoplastic stroma. We studied the expression of 4 extracellular matrix molecules at the protein and messenger RNA levels in monocellular and 2 kinds of coculture systems between human squamous cell carcinoma (ZK-1) and fibroblast (OF-1) cell lines, which may correspond to carcinoma in situ and squamous cell carcinoma, respectively. Squamous cell carcinoma and carcinoma in situ tissue sections were also investigated by immunohistochemistry and in situ hybridization for extracellular matrix. Immunohistochemically, perlecan and tenascin C were localized in carcinoma cells in carcinoma in situ, whereas they were in the stromal space in squamous cell carcinoma. In monocellular culture conditions, expression levels for perlecan, tenascin C, and laminin were more predominant in ZK-1 than in OF-1, although those for fibronectin were more enhanced in OF-1. However, these extracellular matrix expression levels of OF-I were elevated, whereas those of ZK-1 dropped when they were in coculture conditions. The differences between ZK-1 and OF-I were significantly more evident in direct contact (ZK-1/OF-1, 56%-22%) than in indirect contact (63%-39%). These results indicate that oral squamous cell carcinoma cells produce extracellular matrix in the absence of stromal fibroblasts (or in carcinoma in situ) and that they stop producing extracellular matrix in the presence of fibroblasts (or in squamous cell carcinoma). It is hence suggested that stromal fibroblasts after direct contact with invading squamous cell carcinoma cells are more responsible than squamous cell carcinoma cells for the formation of neoplastic stroma, whereas carcinoma in situ cells have to produce and deposit extracellular matrix by themselves to form intraepithelial microstromal spaces. (C) 2012 Elsevier Inc. All rights reserved.

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  • Loss of keratin 13 in oral carcinoma in situ: a comparative study of protein and gene expression levels using paraffin sections 査読

    Hiroko Ida-Yonemochi, Satoshi Maruyama, Takanori Kobayashi, Manabu Yamazaki, Jun Cheng, Takashi Saku

    MODERN PATHOLOGY   25 ( 6 )   784 - 794   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Immunohistochemical loss of keratin (K)13 is one of the most valuable diagnostic criteria for discriminating carcinoma in situ (CIS) from non-malignancies in the oral mucosa while K13 is stably immunolocalized in the prickle cells of normal oral epithelium. To elucidate the molecular mechanism for the loss of K13, we compared the immunohistochemical profiles for K13 and K16 which is not expressed in normal epithelia, but instead enhanced in CIS, with their mRNA levels by in-situ hybridization in formalin-fixed paraffin sections prepared from 23 CIS cases of the tongue, which were surgically removed. Reverse transcriptase-PCR was also performed using RNA samples extracted from laser-microdissected epithelial fragments of the serial paraffin sections in seven of the cases. Although more enhanced expression levels for K16 were confirmed at both the protein and gene levels in CIS in these seven cases, the loss of K13 was associated with repressed mRNA levels in four cases, but not in the other three cases. The results suggest that the loss of K13 is partly due to its gene repression, but may also be due to some unknown post-translational events. Modern Pathology (2012) 25, 784-794; doi:10.1038/modpathol.2011.218; published online 3 February 2012

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  • Short telomeres in an oral precancerous lesion: Q-FISH analysis of leukoplakia 査読

    Junko Aida, Takanori Kobayashi, Takashi Saku, Masatsune Yamaguchi, Naotaka Shimomura, Ken-Ichi Nakamura, Naoshi Ishikawa, Satoshi Maruyama, Jun Cheng, Steven S. S. Poon, Motoji Sawabe, Tomio Arai, Kaiyo Takubo

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   41 ( 5 )   372 - 378   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    OBJECTIVES: A precancerous condition is a lesion that, if left untreated, leads to cancer or can be induced to become malignant. In the oral region, leukoplakia is a lesion that has been regarded as precancerous. In cases of oral carcinoma, we have frequently noticed that a type of leukoplakia histologically demonstrating hyper-orthokeratosis and mild atypia (ortho-keratotic dysplasia; OKD) is often associated with carcinoma, either synchronously or metachronously. Therefore, we consider OKD-type leukoplakia to be a true precancerous lesion. MATERIALS AND METHODS: In an attempt to clarify the relationship between OKD as a precancerous condition in the oral mucosa and telomere length, we estimated telomere lengths in this type of leukoplakia using quantitative fluorescence in situ hybridization, and also quantified the frequency of anaphase-telophase bridges (ATBs) in comparison with squamous cell carcinoma in situ (CIS) and the background tissues of CIS and OKD. RESULTS: Ortho-keratotic dysplasia was frequently associated with squamous cell carcinoma (45.0%) and showed significantly shorter telomeres than normal control epithelium, CIS, or the background of CIS or OKD. The frequency of ATBs was much higher in OKD than in control epithelium or CIS. CONCLUSION: Ortho-keratotic dysplasia appears to be frequently associated with carcinoma, chromosomal instability, and excessively shortened telomeres, not only in the lesion itself but also in the surrounding background. Therefore, when this type of leukoplakia is recognized in the oral region, strict follow-up for oral squamous cell carcinoma is necessary, focusing not only on the areas of leukoplakia, but also the surrounding background.

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  • Intraepithelially entrapped blood vessels in oral carcinoma in-situ 査読

    Akinori Funayama, Satoshi Maruyama, Manabu Yamazaki, Kamal Al-Eryani, Susumu Shingaki, Chikara Saito, Jun Cheng, Takashi Saku

    VIRCHOWS ARCHIV   460 ( 5 )   473 - 480   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    It can be difficult to make a certain diagnosis in case of an oral borderline malignant lesion on hematoxylin-eosin-stained sections only. Furthermore, assessment of surgical margins of borderline lesions is difficult with the naked eye. We set out to determine the topographical distribution of capillary blood vessels within the epithelial zone and to assess its use as an aid for histopathological diagnosis and a framework for clinical assessment of lesional margins using optical techniques, such as narrow-band imaging (NBI) endoscopy. Capillary blood vessels entrapped in the epithelial compartment, which we have designated as intraepithelially entrapped blood vessels (IEBVs), were examined for their frequency, location, and shape in normal mucosa, dysplasia, and carcinoma in-situ (CIS) of the tongue using immunohistochemistry for CD31 and type IV collagen. When counted per unit length of epithelial surface, IEBVs increased in number significantly in CIS (5.6 +/- 2.8), which was two times more than in normal (1.9 +/- 1.6) and dysplastic (2.4 +/- 1.5) epithelia. In addition, IEBVs in CIS had compressed shapes with occasional obstruction or collapse with hemorrhage and were arranged perpendicular to and extending up to the epithelial surface. These characteristic IEBVs in CIS were considered to be generated by complex expansion of rete ridges due to carcinoma cell proliferation within the limited epithelial space determined by the basement membrane. The recognition of IEBVs was helpful in the differential diagnosis of oral CIS, and the present data provide a valuable frame of reference for detecting oral CIS areas using such NBI-based optical devices.

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  • Inflammatory histopathogenesis of nasopalatine duct cyst: a clinicopathological study. 査読

    Tsuneki M, Maruyama S, Yamazaki M, Abe T, Adeola HA, Cheng J, Nishiyama H, Hayashi T, Kobayashi T, Takagi R, Funayama A, Saito C, Saku T

    Oral Diseases   19 ( 4 )   415 - 424   2012年5月

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  • Podoplanin expression profiles characteristic of odontogenic tumor-specific tissue architectures 査読

    Masayuki Tsuneki, Satoshi Maruyama, Manabu Yamazaki, Jun Cheng, Takashi Saku

    PATHOLOGY RESEARCH AND PRACTICE   208 ( 3 )   140 - 146   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER GMBH, URBAN & FISCHER VERLAG  

    Podoplanin, a representative immunohistochemical marker for lymphatic endothelial cells, is also expressed in many other kinds of cancer cells, although its pathophysiological function is largely unknown. Our aim was to determine immunolocalization modes of podoplanin among odontogenic tumors to discuss possible roles of podoplanin in their characteristic tissue architecture formation. Immunohistochemical profiles of podoplanin were investigated in 40 surgical specimens from ameloblastoma (AM), adenomatoid odontogenic tumor (AOT), calcifying cystic odontogenic tumor (CCOT), and keratocystic odontogenic tumor (KCOT) in comparison with those of proliferating cell nuclear antigen (PCNA), integrin beta 1, fibronectin, and matrix metalloproteinase 9 (MMP-9). Podoplanin was localized in the basal cell layer or in the peripheral zone of AM foci. It was found in spindle-shaped tumor cells of AOT, in both the basal and polyhedral cells of CCOT, and in the basal and parabasal cells of KCOT linings. Podoplanin-positive (+) cells were located within areas of PCNA+ cells, and integrin beta 1 was localized in the cell membrane of podoplanin+ cells in the intercellular space where fibronectin and MMP-9 were deposited. In conclusion, podoplanin+ cells and areas in odontogenic tumors are in close associations with extracellular matrix signalings as well as cell proliferation. (C) 2012 Elsevier GmbH. All rights reserved.

    DOI: 10.1016/j.prp.2011.12.016

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  • Differential expression of perlecan receptors, α-dystroglycan and integrin β1, before and after invasion of oral squamous cell carcinoma. 査読

    Ahsan MS, Yamazaki M, Maruyama S, Kobayashi T, Ida-Yonemochi H, Hasegawa M, Henry Ademola A, Cheng J, Saku T

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   40 ( 7 )   552 - 559   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1600-0714.2010.00990.x

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  • Nuclear translocation of β-catenin synchronized with loss of E-cadherin in oral epithelial dysplasia with a characteristic two-phase appearance. 査読

    Alvarado CG, Maruyama S, Cheng J, Ida-Yonemochi H, Kobayashi T, Yamazaki M, Takagi R, Saku T

    Histopathology   59 ( 2 )   283 - 291   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1365-2559.2011.03929.x

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  • Emergence of keratin 17 vs. loss of keratin 13: Their reciprocal immunohistochemical profiles in oral carcinoma in situ 査読

    Toshihiko Mikami, Jun Cheng, Satoshi Maruyama, Takanori Kobayashi, Akinori Funayama, Manabu Yamazaki, Henry A. Adeola, Lanyan Wu, Susumu Shingaki, Chikara Saito, Takashi Saku

    ORAL ONCOLOGY   47 ( 6 )   497 - 503   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    To evaluate differential expressions for keratin (K) subtypes 13 and 17 in oral borderline malignancies, we examined 67 surgical specimens of the oral mucosa for their immunohistochemical profiles. From those specimens, 173 foci of epithelial dysplasia, 152 foci of carcinoma in situ (CIS), and 82 foci of squamous cell carcinoma (SCC) were selected according to our diagnostic criteria, along with 20 areas of normal epithelia. In normal epithelia, there was no K17 positivity (0%), whereas definite K13 positivity (100%) was observed. The same tendencies were obtained in mild (undefined) and moderate (true) epithelial dysplasias (K17: 0%; K13: 100%). In contrast, all CIS (100%) had K17 positivities, while K13 positivities were lost in many of them (7%). Similar tendencies were confirmed in invasive SCC (K17: 100%, K13: 4%). Simultaneous immunopositivities for K17 and K13 were found only in SCC (7%) and CIS (4%) foci with distinct keratinization. These foci also showed K10 positivities, though K10 positive areas were not identical to K13 positive areas. The results indicate that expressions of K17 and K13 are reciprocal in oral epithelial lesions and that the K17 emergence is related to malignancies. (C) 2011 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.oraloncology.2011.03.015

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  • Complication of adenoid cystic carcinoma and sialolithiasis in the submandibular gland: report of a case and its etiological background 査読

    M. Hasegawa, J. Cheng, S. Maruyama, M. Yamazaki, A. Iida, R. Takagi, R. Tanaka, T. Hayashi, C. Saito, T. Saku

    INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   40 ( 6 )   647 - 650   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CHURCHILL LIVINGSTONE  

    The authors report a case of adenoid cystic carcinoma (ACC) complicated with sialolithiasis of the submandibular gland. The patient was a 43-year-old female with a history of papillotubular carcinoma of the breast almost at the same time. She had noticed a swelling in her sublingual area for 10 years, which was later diagnosed by her dentist to be due to a sialolith in the left submandibular gland. After several years of observation, the patient was referred to have her left submandibular gland, containing the stone, surgically removed with a diagnosis of atrophic sialadenitis. Histopathologically, the submandibular gland was extensively replaced with fibrous granulation tissue, in which there were small but invasive foci of ACC. The present case indicates that ACC could arise in the background of chronic sialadenitis. It is suggested that long-standing sialadenitis cases should be carefully examined to exclude suspicion of malignancy before surgery.

    DOI: 10.1016/j.ijom.2010.11.009

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  • Acetic Acid Treatment for Wrinkle-Free Oral Mucosal Epithelia in Paraffin Section Preparation 査読

    Md. Shahidul Ahsan, Satoshi Maruyama, Jun Cheng, Kamal Al-Eryani, Manabu Yamazaki, Mayumi Hasegawa, Masayuki Tsuneki, Takashi Saku

    MICROSCOPY RESEARCH AND TECHNIQUE   74 ( 3 )   264 - 268   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    For histopathological assessment of oral borderline malignancies, it is important to carefully detect subtle epithelial changes on fully stretched tissue sections. However, it is not generally easy to obtain wrinkle-free sections when using formalin-fixed paraffin-embedded oral mucosal samples. Since acetic acid treatment is already utilized for large brain tissue sections, we examined whether that treatment was also effective for oral mucosal tissues containing normal to malignant epithelial lesions. Paraffin sections were floated in various concentrations of acetic acid for 10 min after stretching in water for 1 min, then wrinkle formations were examined using hematoxylin and eosin staining, as well as for staining intensity with keratin immunohistochemistry. Wrinkles were formed in both epithelial and connective tissue zones of sections treated with less than a 40-mM (0.25%) concentration of acetic acid. In contrast, treatments with concentrations at 80 mM (0.5%) and higher resulted in cracking between the epithelial layer and lamina propria, as well as poor immunohistochemical results for keratins 13 and 17, even though the wrinkles completely disappeared. These results indicate that 40 mM is the optimal concentration of acetic acid solution to prevent wrinkles in the epithelial layer while maintaining the immunohistochemical qualities of oral mucosa tissue sections, especially those containing borderline malignant epithelial lesions. Microsc. Res. Tech. 74: 264-268,2011. (C) 2010 Wiley-Liss, Inc.

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  • A case of desmoplastic ameloblastoma arising in the maxillary alveolus: the origin and time-course changes in the early stage of tumour development observed on dental radiographs 査読

    K. Katsura, S. Maruyama, M. Suzuki, T. Saku, R. Takagi, T. Hayashi

    DENTOMAXILLOFACIAL RADIOLOGY   40 ( 2 )   126 - 129   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BRITISH INST RADIOLOGY  

    In this article we report a case of desmoplastic ameloblastoma in which chronological changes in the early development can be observed on dental radiographs. The tumour grew very slowly and did not appear to have a strong potential for local extension like typical ameloblastomas. Radiological findings of our case suggest the tumour arose from the periodontal membrane. However, it was not possible to obtain conclusive histopathological evidence. Dentomaxillofacial Radiology (2011) 40, 126-129. doi: 10.1259/dmfr/55423624

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  • Oral cancer in Myanmar: a preliminary survey based on hospital-based cancer registries 査読

    Htun Naing Oo, Yi Yi Myint, Chan Nyein Maung, Phyu Sin Oo, Jun Cheng, Satoshi Maruyama, Manabu Yamazaki, Minoru Yagi, Faleh A. Sawair, Takashi Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   40 ( 1 )   20 - 26   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    The occurrence of oral cancer is not clearly known in Myanmar, where betel quid chewing habits are widely spread. Since betel quid chewing has been considered to be one of the important causative factors for oral cancer, the circumstantial situation for oral cancer should be investigated in this country. We surveyed oral cancer cases as well as whole body cancers from two cancer registries from Yangon and Mandalay cities, both of which have representative referral hospitals in Myanmar, and we showed that oral cancer stood at the 6th position in males and 10th in females, contributing to 3.5% of whole body cancers. There was a male predominance with a ratio of 2.1:1. Their most frequent site was the tongue, followed by the palate, which was different from that in other countries with betel quid chewing habits. About 90% of male and 44% of female patients had habitual backgrounds of chewing and smoking for more than 15 years. The results revealed for the first time reliable oral cancer frequencies in Myanmar, suggesting that longstanding chewing and smoking habits are etiological backgrounds for oral cancer patients.

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  • Enhanced Expression of Podoplanin in Oral Carcinomas in situ and Squamous Cell Carcinomas 査読

    Akinori Funayama, Jun Cheng, Satoshi Maruyama, Manabu Yamazaki, Takanori Kobayashi, Mei Syafriadi, Sukalyan Kundu, Susumu Shingaki, Chikara Saito, Takashi Saku

    PATHOBIOLOGY   78 ( 3 )   171 - 180   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Objective: Podoplanin, a known lymphatic endothelial cell marker, has been reported to be expressed in various types of cancer. To elucidate the expression of podoplanin in precancerous lesions, we examined the immunohistochemical profiles of podoplanin in oral squamous epithelial lesions. Method: We studied a total of 298 foci of squamous cell carcinoma (SCC), carcinoma in situ (CIS), epithelial dysplasia, and hyperplastic and/or normal epithelial lesions by immunohistochemistry using D2-40. Results: There was no positivity for podoplanin in normal or hyperplastic epithelia, while all of the CIS and SCC foci stained positive. Approximately one third of the mild dysplasia foci (10 of 36 foci, 28%) and 80% of moderate dysplasia foci (78/98) showed grade 1 positive reactions (positive only in the 1st layer). Grade 2 reactions (up to 4th layer) were seen in 4 of 98 moderate dysplasia foci (4%), 29 of 74 CIS foci (39%), and 3 of 30 SCC foci (10%). Grade 3 reactions (to more than 5th layer) were found in 35 (47%) CIS foci and 26 (87%) SCC foci. Conclusions: The relationship between the present histological categorization and podoplanin grade was statistically significant. D2-40 expression is considered to be related to the severity of oral precancerous lesions. Copyright (C) 2011 S. Karger AG, Basel

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  • Tumor mimicking actiomycosis of the upper lip: report of two cases 査読

    Kayo Kuyama, Yan Sun, Kenji Fukui, Satoshi Maruyama, Eriko Ochiai, Masahiko Fukumoto, Nobuyuki Ikeda, Toshihiro Kondoh, Kimiharu Iwadate, Ritsuo Takagi, Takashi Saku, Hirotsugu Yamamoto

    Oral Med Pathol   15   95 - 99   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3353/omp.15.95

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  • Combined immunohistochemistry for the differential diagnosis of cystic jaw lesions: its practical use in surgical pathology 査読

    Masayuki Tsuneki, Manabu Yamazaki, Jun Cheng, Satoshi Maruyama, Takanori Kobayashi, Takashi Saku

    HISTOPATHOLOGY   57 ( 6 )   806 - 813   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Combined immunohistochemistry for the differential diagnosis of cystic jaw lesions: its practical use in surgical pathology
    Aims:
    Histopathological distinction of cystic jaw lesions, including odontogenic tumours, is challenging because their lining epithelia, which are basically stratified squamous epithelia, resemble each other, especially when they become hyperplastic from inflammatory reaction. The aim of this study was to seek practical measures to differentiate such lesions.
    Methods and results:
    Nineteen surgical specimens from unicystic ameloblastomas (UAs), 17 from keratocystic odontogenic tumours (KCOTs), 13 from dentigerous cysts (DCs), 10 from lateral periodontal cysts (LPCs) and 20 from radicular cysts (RCs), all of which contained both typical flat and rete-peg-shaped lining epithelia, were examined for their immunohistochemical profiles. Among them, keratin (K) 10, K17, perlecan, proliferating cell nuclear antigen (PCNA) and UEA-I lectin binding (UEA) were selected as useful immunohistochemical markers for their differential diagnosis. K10 was positive (+) in KCOT and DC. K17 was not present in RC. Perlecan was found in UA, KCOT and LPC. PCNA+ cells were found frequently in UA and KCOT. These localization patterns were constant even when linings were not flat.
    Conclusions:
    Using a combination of six kinds of immunohistochemical pattern, it is now possible to discriminate reliably and objectively these five cystic jaw lesions in routine practice.

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  • Histopathological varieties of oral carcinoma in situ: Diagnosis aided by immunohistochemistry dealing with the second basal cell layer as the proliferating center of oral mucosal epithelia 査読

    Takanori Kobayashi, Satoshi Maruyama, Jun Cheng, Hiroko Ida-Yonemochi, Minoru Yagi, Ritsuo Takagi, Takashi Saku

    PATHOLOGY INTERNATIONAL   60 ( 3 )   156 - 166   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    To make reproducible diagnoses for oral carcinoma in situ (CIS), combined immunohistochemistry directed at the positioning of squamous cell proliferation (Ki-67) and differentiation (keratin (K) 13 and K19) was used, both of which support histological evaluations by providing biological evidence. Normal/hyperplastic epithelia was defined by K19+ cells only in the first basal layer, K13+ cells in the third basal and upper layers, and sporadic Ki-67+ cells in the second basal layer. These profiles indicated that a proliferating center of the oral epithelium is located in the parabasal cell layer, and K19 and K13 can be regarded as markers for basal and prickle cells, respectively. Epithelial dysplasia was characterized by irregular stratification of Ki-67+ cells and the absence of K19/K13 in proliferating cells. Irregular emerging of K19+ and K13+ cells in proliferating foci with unique stratification of atypical Ki-67+ cells indicated CIS. When the definition was applied, surgical margins in 172 recurrent cases were shown to contain CIS (39.4%) and squamous cell carcinoma (55.8%), indicating that the new diagnostic criteria for CIS reflected clinical behaviors of the cases. The results indicate that oral CIS contain more histological variations, especially those with definite keratinization, than what had been previously defined.

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  • Metastasis-associated genes in oral squamous cell carcinoma and salivary adenoid cystic carcinoma: a differential DNA chip analysis between metastatic and nonmetastatic cell systems 査読

    Satoshi Maruyama, Jun Cheng, Manabu Yamazaki, Xiao-jian Zhou, Zhi-yuan Zhang, Rong-gen He, Takashi Saku

    CANCER GENETICS AND CYTOGENETICS   196 ( 1 )   14 - 22   2010年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Overall modes of differential gene expressions were analyzed between human oral/salivary carcinoma cell systems with (MK-1 and ACCM) and without (ZK-1/ZK-2 and ACC2/ACC3) metastatic potential by using micro-array analysis with cancer-associated DNA chips to determine the kinds of genes associated with metastatic behaviors. MK-1 and/or ACCM showed lower levels of gene expression in extracellular matrix-related molecules, such as collagen type IV, laminin, and adhesion molecules such as cadherin 2, but higher levels of genes which control extracellular matrix degradation, such as MMP 9, as well as cell growth and cycle, such as FGF7 and cyclin D1. Among the differentially expressed genes, similar protein expression tendencies for FGF7, laminin, cyclin D1, and collagen type IV were confirmed by immunofluorescence. Metastatic potentials of oral/salivary carcinoma cells seem to have resulted from certain combinations of over-/underexpression of the genes, which were responsible for extracellular matrix metabolism and cell growth in particular. (C) 2010 Elsevier Inc. All rights reserved.

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  • Oral solitary fibrous tumor: a cytogenetic analysis of tumor cells in culture with literature review 査読

    Wael M. Swelam, Jun Cheng, Hiroko Ida-Yonemochi, Satoshi Maruyama, Takashi Saku

    CANCER GENETICS AND CYTOGENETICS   194 ( 2 )   75 - 81   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Solitary fibrous tumor (SFT) is an uncommon spindle-cell neoplasm of mesenchymal origin. Because the pathogenetic background of SFT is still controversial, cytogenetic analysis could help in tumor diagnosis and prognosis. In this study, cultured SFT cells from a lower lip lesion that presented characteristic immunopositivity for CD34, vimentin, CD99, and BCL2 showed a unique cytogenetic finding: 46,XX,inv(2)(p21q35),t(3;12)(q25;q15). To our knowledge, this is the third report of cytogenetic result of a case involving the oral cavity. The SFT cells in culture that maintained their immunohistochemical expression of diagnostic molecules, showed unique chromosomal changes previously unreported when compared with already documented ones. Our data suggest that the complicated pathogenetic nature of SFT is possibly tumor- or organ-related. (C) 2009 Elsevier Inc. All rights reserved.

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  • Establishment and characterization of pleomorphic adenoma cell systems: an in-vitro demonstration of carcinomas arising secondarily from adenomas in the salivary gland 査読

    Satoshi Maruyama, Jun Cheng, Susumu Shingaki, Takashi Tamura, Shuichi Asakawa, Shinsei Minoshima, Yoshiko Shimizu, Nobuyoshi Shimizu, Takashi Saku

    BMC CANCER   9   247   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Among the salivary gland carcinomas, carcinoma in pleomorphic adenoma has been regarded as a representative carcinoma type which arises secondarily in the background of a pre-existent benign pleomorphic adenoma. It is still poorly understood how and which benign pleomorphic adenoma cells transform into its malignant form, carcinoma ex pleomorphic adenoma.
    Methods: We have established five cell systems from a benign pleomorphic adenoma of the parotid gland of a 61-year-old woman. They were characterized by immunofluorescence, classical cytogenetics, p53 gene mutational analysis, fluorescence in-situ hybridization, and histopathological and immunohistochemical examinations of their xenografts, to demonstrate their potency of secondary transformation.
    Results: We established and characterized five cell systems (designated as SM-AP1 to SM-AP5) from a benign pleomorphic adenoma of the parotid gland. SM-AP1 to SM-AP3 showed polygonal cell shapes while SM-AP4 and SM-AP5 were spindle-shaped. SM-AP1-3 cells were immunopositive for keratin only, indicating their duct-epithelial or squamous cell differentiation, while SM-AP4/5 cells were positive for both keratin and S-100 protein, indicating their myoepithelial cell differentiation. Chromosome analyses showed numeral abnormalities such as 5n ploidies and various kinds of structural abnormalities, such as deletions, translocations, derivatives and isodicentric chromosomes. Among them, der(9)t(9;13)(p13.3;q12.3) was shared by all five of the cell systems. In addition, they all had a common deletion of the last base G of codon 249 (AGG to AG_) of the p53 gene, which resulted in generation of its nonsense gene product. Transplanted cells in nude mice formed subcutaneous tumors, which had histological features of squamous cell carcinoma with apparent keratinizing tendencies. In addition, they had ductal arrangements or plasmacytoid appearances of tumor cells and myxoid or hyaline stromata, indicating some characteristics of pleomorphic adenoma.
    Conclusion: This study demonstrates in vitro that certain cell types from pleomorphic adenoma are able to clone and survive over a long term and develop subcutaneous tumors in nude mice. The histological features of squamous cell carcinoma from the transplanted cell systems in nude mice might suggest a secondary onset of malignancy from a pre-existing benign adenoma.

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  • Lymphoepithelial cyst of the parotid gland: its possible histopathogenesis based on clinicopathologic analysis of 64 cases 査読

    Lanyan Wu, Jun Cheng, Satoshi Maruyama, Manabu Yamazaki, Masayuki Tsuneki, Yong Lu, Zhixiu He, Yage Zheng, Zhiyu Zhou, Takashi Saku

    HUMAN PATHOLOGY   40 ( 5 )   683 - 692   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Sixty-four cases of lymphoepithelial cysts of the parotid gland, the largest scale collection in the literature, were clinicopathologically analyzed for their possible pathogenesis. All 64 cases were unilateral, 27 left and 37 right. There were 28 male and 36 female patients with a ratio of 1:1.3. The mean age of the patients was 52.0 years, and their average duration of symptoms was 29.3 months. The mean longest diameter of the cysts was 3.0 cm. Histologically, lymphoepithelial cysts were classified into 3 subtypes: type I, a cystic dilation of ducts within parotid glands (9 cases, 14.1%); type II, partially demarcated cystic lesions with lymphoid stroma (27, 42.2%); type III, well-encapsulated cystic lesions with lymphoid stroma containing lymph follicular structures (28, 43.8%). Based on immunohistochemical results for lymphocyte/macrophage (CD20/CD45RO/IgG4), cell cycle (Ki-67), and lymphatic (D2-40) markers, the lymphoid stroma was shown to have neither the usual lymph follicular distributions of T/B cells nor lymph sinus structures. No viral infection was confirmed. The results seemed to indicate that the lymphoid stroma were induced along with the growth of the cystic dilatation of ducts within sialadenitis, which were neither induced by Epstein-Barr virus nor HIV infections, and that the formation of lymphoepithelial cysts was completed by demarcation, which should have been a kind of granulation tissue reaction, from the parotid parenchyma but did not arise from intraparotid lymph nodes. (C) 2009 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.humpath.2008.10.012

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  • Keratinocyte growth factor colocalized with perlecan at the site of capsular invasion and vascular involvement in salivary pleomorphic adenomas 査読

    Satoshi Maruyama, Jun Cheng, Manabu Yamazaki, Airu Liu, Takashi Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   38 ( 4 )   377 - 385   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Capsular invasion is often observed in daily pathologic diagnosis of pleomorphic adenomas, although neither actual information about its occurrence nor molecular mechanisms leading to their invasive activities have been reported. In this study, our aim was to elucidate the mode and the frequency of capsular invasion in this tumor and to characterize the tumor cell arrangement at the site of capsular invasion.
    The mode and frequency of capsular invasion of salivary pleomorphic adenomas were histopathologically examined in 104 surgical specimens of pleomorphic adenoma, and stromal characteristics, and tumor cell arrangements at the sites of capsular invasion were immunohistochemically investigated.
    A total of 353 areas with capsular invasive changes were collected from 104 cases. The mode of capsular invasion was classified into two types: type I: intracapsular invasion (247 areas, 70%) and type II: capsular penetration (106 areas, 30%). Myxoid stroma, which was perlecan-immunopositive (+), was shared by both type I and type II sites, while tumor cell foci containing ductal structures were predominant in type II sites. These foci were composed of KGF(+) and FGFR2(+) cells. In addition, apparent vascular involvement was recognized in 31 tumors (29.8%).
    The results suggest that pleomorphic adenoma cells are able to invade into the capsule and involve blood vessels when they are situated in perlecan-rich milieu, which accelerate KGF signaling.

    DOI: 10.1111/j.1600-0714.2008.00742.x

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  • Matrix metalloproteinase 7 and perlecan in oral epithelial dysplasia and carcinoma in situ: An aid for histopathologic recognition of their cell proliferation centers 査読

    W. M. Tilakaratne, W. M. Tilakaratne, T. Kobayashi, H. Ida-Yonemochi, W. Swelam, M. Yamazaki, T. Mikami, C. G. Alvarado, A. Md Shahidul, S. Maruyama, J. Cheng, T. Saku, T. Saku

    J Oral Pathol Med   38   348 - 355   2009年4月

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  • Adenoid cystic carcinoma of sublingual gland involving the submandibular duct 査読

    Saito M, Nishiyama H, Maruyama S, Oda Y, Saku T, Hayashi T

    Dentomaxillofac Radiol   37 ( 7 )   421 - 424   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1259/dmfr/31299961

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  • Perlecan-rich epithelial linings as a background of proliferative potentials of keratocystic odontogenic tumor 査読

    Masayuki Tsuneki, Jun Cheng, Satoshi Maruyama, Hiroko Ida-Yonemochi, Motowo Nakajima, Takashi Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   37 ( 5 )   287 - 293   2008年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    BACKGROUND: The intraepithelial deposit of perlecan, a basement membrane-type heparan sulfate (HS) proteoglycan, has been demonstrated in neoplastic conditions such as salivary gland tumors, odontogenic tumors, and oral carcinoma in situ. Our aim was to determine whether perlecan turnover was enhanced in the lining cells of keratocystic odontogenic tumor (KCOT), which had been recently renamed from odontogenic keratocyst because of its accumulated evidence of neoplasm, as a possible background for neoplastic proliferation.
    METHODS: Ten surgical specimens from each of KCOT, dentigerous cyst, and radicular cyst were examined for the expressions of perlecan core protein, HS chains, heparanase, and Ki-67 by immunohistochemistry and in situ hybridization.
    RESULTS: In KCOT, perlecan core protein and HS chains were localized on the cell border from the parabasal to subkeratinized layers of the lining epithelium. Heparanase was localized in a similar fashion to those for perlecan and HS chains but was within the cytoplasm. mRNA signals for perlecan core protein and heparanase were mostly compatible with their protein signals. Ki-67-positive cells were localized mainly in the second basal cell layers with definitely higher labeling indices (approximately 31.3%, second layer). In contrast to KCOT, dentigerous cysts and radicular cysts had no perlecan, HS chains, and heparanase deposition in their linings with extremely lower Ki-67 indices (0.4-0.8%).
    CONCLUSION: The result suggests that the characteristic intra-lining-epithelial deposit of perlecan in KCOT, which has never been seen in other cystic jaw lesions, is a new evidence supporting the neoplastic nature of KCOT.

    DOI: 10.1111/j.1600-0714.2007.00620.x

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  • A case report of multiple-drug-induced gingival overgrowth with TIMP-3 over-expression 査読

    Kubota T, Itagaki M, Morozumi T, Maruyama S, Nakasone N, Shimizu T, Saku T, Yoshie H

    Oral Medicine & Pathology   12 ( 4 )   141 - 148   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3353/omp.12.141

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  • High relative frequency of oral squamous cell carcinoma in Yemen: Qat and tobacco chewing as its aetiological background

    Faleh A. Sawair, Ammar Al-Mutwakel, Kamal Al-Eryani, Ameera Al-Surhy, Satoshi Maruyama, Jun Cheng, Ali Al-Sharabi, Takashi Saku

    INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH   17 ( 3 )   185 - 195   2007年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    To study the association of qat chewing with the occurrence of oral cancer, the frequency of oral cancer among whole body cancers and the patients' histories of tobacco consumption and qat chewing were examined in Yemen where qat chewing has been most popular. All primary malignant tumors listed in the surgical pathology files at Al-Thawra Hospital, University of Sana'a, in the year 2004 were analyzed, and the patients' histories of tobacco consumption and qat chewing were examined. A total of 649 cases of primary malignant tumors (348, 53.6% males and 301, 46.4% females) were extracted. Oral cancer was the most frequent body cancer in both males (17.2%) and females (19.6%). Squamous cell carcinoma (SCC) was the most frequent oral cancer (84%), and the tongue (42%), gingiva (23%) and buccal mucosa (20%) were the most common sites. Among the 119 patients with oral cancer, information on chewing habits and smoking was obtained in 92 patients (77.3%). There were 70 tobacco chewers (76.1%), 55 qat chewers (59.8%), and 22 smokers (23.9%). Simultaneous chewing of tobacco and qat was found in 48 cases (52.2%). The present survey has disclosed for the first time that oral SCC is the most frequent cancer in this study area in Yemen, and that the high relative frequency of oral SCC may be related to the habits of chewing tobacco and qat.

    DOI: 10.1080/09603120701254813

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  • Lymphatic involvement in the histopathogenesis of mucous retention cyst

    Sukalyan Kundu, Jun Cheng, Satoshi Maruyama, Makoto Suzuki, Hiroyuki Kawashima, Takashi Saku

    PATHOLOGY RESEARCH AND PRACTICE   203 ( 2 )   89 - 97   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER GMBH, URBAN & FISCHER VERLAG  

    Mucous retention cyst results from extravasation of saliva. Our intent was to study the role of lymphatics in its pathogenesis.
    Twenty-three surgical specimens of mucous retention cyst of the lip were examined for involvement of lymphatic vessels by a comparative immunohistochemical demonstration of lymphatic and blood vascular endothelial cells, as well as lymphatic and salivary contents.
    Mucous retention cysts were histopathologically classified into three stages: early, intermediate, and advanced. In the early stage, there was diffuse extravasation of mucous material in the interstitium of the lamina propria or the submucosal layer of the oral mucosa. In the intermediate stage, lymphatics, which were clearly revealed and immunohistochemically distinguished from blood vessels by monoclonal antibody D2-40, were dilated and finally ruptured, leaving fragments of lymphatic walls in the periphery of mucous pools. In the advanced stage, thick cyst walls of granulation tissue were formed around mucous retention. Lymphatics were no longer involved in the granulation tissue wall, which was actively driven by blood vessel formation.
    The results suggest that the lymphatic rupture seems to contribute to the enlargement in the pathogenesis of mucous retention cyst. (c) 2006 Elsevier GmbH. All rights reserved.

    DOI: 10.1016/j.prp.2006.11.003

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  • Extracellular matrix remodeling in oral submucous fibrosis: its stage-specific modes revealed by immunohistochemistry and in situ hybridization

    H Utsunomiya, WM Tilakaratne, K Oshiro, S Maruyama, M Suzuki, H Ida-Yonemochi, J Cheng, T Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   34 ( 8 )   498 - 507   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    BACKGROUND: Oral submucous fibrosis (OSF) is a chewing habit-related pre-cancerous condition of the oral mucosa affecting predominantly south Asians. It is histopathologically characterized by epithelial atrophy and fibrosis of the subepithelial connective tissue. Fibrosis extends all the way into the muscle layer, leading to difficulty in mouth opening. However, the dynamics of extracellular matrix (ECM) remodeling with OSF progression is largely unknown.
    METHODS: Forty biopsy specimens of OSF and 10 of normal buccal mucosa were examined for expression/deposition modes of eight ECM molecules by histochemistry, immunohistochemistry, and in situ hybridization.
    RESULTS: In the early stage of OSF, tenascin, perlecan, fibronectin, collagen type III were characteristically enhanced in the lamina propria and the submucosal layer. In the intermediate stage, the ECM molecules mentioned above and elastin were extensively and irregularly deposited around muscle fibers. In the advanced stage, such ECM depositions decreased and were entirely replaced with collagen type I only. Their gene expression levels varied with progression of fibrosis, but the mRNA signals were confirmed in fibroblasts in the submucosal fibrotic areas.
    CONCLUSIONS: The results indicate that the ECM remodeling steps in OSF are similar to each phase of usual granulation tissue formation. Restricted mouth opening may be a result of loss of variety of ECM molecules including elastin into the homogeneity of collagen type I replacing muscle fibers.

    DOI: 10.1111/j.1600-0714.2005.00339.x

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  • Establishment and characterization of new cell lines derived from melanotic neuroectodermal tumor of infancy arising in the mandible

    H Metwaly, J Cheng, S Maruyama, K Ohshiro, Suzuki, I, Y Hoshina, T Saku

    PATHOLOGY INTERNATIONAL   55 ( 6 )   331 - 342   2005年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Three cell systems (MINT1/2/3) derived from a melanotic neuroectodermal tumor of infancy (MNTI) arising in the mandible of a 1-month-old newborn boy have been established, and their cytological natures have been characterized. The cells had immunopositivities for pan-keratin, vimentin, neuron-specific enolase, S-100 protein and melanoma-associated antigen (HMB-45). These immunohistochemical phenotypes were basically the same as those observed in tissue sections, in which, synaptophysin, myelin basic protein, c-myc gene products, carcinoembryonic antigen, and epithelial membrane antigen were also immunolocalized in tumor cells. Karyotyping analyzes revealed that the chromosome numbers of the three cell systems ranged from 60 to 67 with 3n ploidies, and that there were many structural aberrations, such as del(11)(q13), del(22)(q13), add(2)(p11), add(7)(q22), extra copies for chromosomes 1, 2, 3, 5, 7, 9, 10, 11, 12, 16, 20, and 22, der(9)t(9;13)(p13;q12)add(9)(q34), and der(13;21)(q10;q10), which were shared by the three cell systems, while der(19)t(11;19)(q13;p13) was found in MINT1 and MINT3. When stimulated by endothelin-3 and vitamin D-3, the cells had spinous cell shapes with immunopositivities for HMB-45, neurofilament protein and glial fibrillary acidic protein, which indicated more neural differentiation. The established cell systems will be useful for further investigation on the molecular and genetic basis of MNTI to understand its pathogenesis, which is largely unknown.

    DOI: 10.1111/j.1440-1827.2005.01833.x

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  • Vascular endothelial growth factor in salivary pleomorphic adenomas: one of the reasons for their poorly vascularized stroma

    W Swelam, H Ida-Yonemochi, S Maruyama, K Ohshiro, J Cheng, T Saku

    VIRCHOWS ARCHIV   446 ( 6 )   653 - 662   2005年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    To better understand the poorly vascularized background of the stroma of pleomorphic adenomas, we attempted to determine the expression of molecules related to blood vessels and hypoxic conditions in pleomorphic adenoma. Surgical specimens and tumor cells in primary culture of salivary pleomorphic adenomas were used for immunohistochemistry for CD31, vascular endothelial growth factor (VEGF) and its receptors Flk-1 and Flt-1, as well as for hypoxia markers, such as hypoxia-inducible factor-1 alpha (HIF-1 alpha) and lactate dehydrogenase-1 (LDH). At the same time, alternative splicing modes of the VEGF gene and expression levels of the HIF-1 alpha gene were analyzed in surgical specimens by means of reverse-transcription polymerase chain reaction (RT-PCR) and direct sequencing of the PCR products. In addition to co-immunolocalization with CD31+ vascular endothelial cells, VEGF and its receptors were demonstrated in normal duct epithelial and myoepithelial cells as well as in tumor cells in ductal structures and in myxochondroid stromata. Immunolocalizations for HIF-1 alpha and LDH were confirmed in the VEGF-positive area. Immunofluorescence signals for VEGF and others were confirmed in pleomorphic adenoma cells in culture. RT-PCR results showed that there were at least four splicing modes of the VEGF gene, among which VEGF(121) was most enhanced, and higher HIF-1 alpha levels in pleomorphic adenomas. The results suggest that pleomorphic adenoma cells produce VEGF in several functional forms for their own proliferation or differentiation, and that the VEGF expression is controlled by hypoxic circumstances of poorly vascularized pleomorphic adenomas.

    DOI: 10.1007/s00428-005-1219-1

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  • Solitary fibrous tumor of the lower lip involving minor salivary gland components: Report of a case and review of the literature of salivary gland cases

    Wael Swelam, Hiroko Ida-Yonemochi, Satoshi Maruyama, Terué Ikarashi, Junichi Fukuda, Ritsuo Takagi, Takafumi Hayashi, Takashi Saku

    Oral Oncology Extra   40 ( 10 )   107 - 112   2004年

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    記述言語:英語   出版者・発行元:Elsevier BV  

    A case of solitary fibrous tumor of the Lip is described. A 65-year-old Japanese woman had a painless mass in her lower lip that gradually increased in size and finally ulcerated. Computed tomography revealed a well-demarcated submucosal mass. On the cut surface, the tumor was well-circumscribed, solid, and yellowish-white with small cystic spaces. Histopathologically, it was encapsulated and consisted of an interlacing proliferation of spindle-shaped cells immunopositive for CD34, vimentin, Bcl-2, and CD99, with scattered salivary glandular structures with irregular cellular arrangements. This is the first case report of solitary fibrous tumor of the lip with reactive hyperplasia of minor salivary gland components based on our review of the literature. © 2004 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.ooe.2004.06.002

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  • Castleman's disease of the buccal mucosa: Report of a case and review of the literature of head and neck cases

    S Maruyama, N Hao, J Cheng, K Horino, M Ohnishi, M Fukushi, M Fujii, T Saku

    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS   93 ( 3 )   305 - 310   2002年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MOSBY, INC  

    A case of Castleman's disease occurring in the buccal mucosa is described. An 84-year-old woman noticed that a mass in the left buccal mucosa that had been present for half a year. Computed tomography revealed a well-demarcated submucosal tumor, measuring 4.0 x 3.0 x 2.0 cm. The patient received no treatment at this time, and continued growth of the mass was observed. After incisional biopsy, the lesion was surgically removed. Histologically, the tumor consisted of an enlarged lymph node with conspicuous lymph follicles, in which vascular channels and deposits of eosinophilic material were noted. Laboratory examination showed an increase of serum antibody level of cytomegalovirus but of no other viruses. The patient was followed up for 11/2 years, with no clinical evidence of recurrence. This is the first report of Castleman's disease presenting in an oral site.

    DOI: 10.1067/moe.2002.120026

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  • Sebaceous lymphadenoma of the lip: Report of a case of minor salivary gland origin

    Satoshi Maruyama, Jun Cheng, Tatsuo Inoue, Ritsuo Takagi, Takashi Saku

    Journal of Oral Pathology and Medicine   31 ( 4 )   242 - 243   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A case of sebaceous lymphadenoma occurring in the lip of a 73-year-old female is described. The patient had noticed a painless mass in the region of her upper lip for a year. The surgically removed tumor, measuring about 10mm in diameter, was located just beneath the lip mucosa, expanding into the submucosal and muscle layer. Histologically, the tumor was well encapsulated and consisted of scattered round-shaped islands of small squamous epithelial cells with focal but apparent sebaceous differentiation in a background of lymphoid stroma. This is the first case report of sebaceous lymphadenoma of minor salivary gland origin.

    DOI: 10.1034/j.1600-0714.2002.310409.x

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MISC

  • 口腔細胞診の従来法とLBC法において判定精度に影響を与える臨床病理学的因子の検討

    河原田壮史, 河原田壮史, 丸山智, 山崎学, 阿部達也, 上野山敦士, 秋森俊行, 秋森俊行, 小島拓, 小島拓, 冨原圭, 小林正治, 田沼順一

    日本口腔診断学会総会プログラム・抄録集   35th   2022年

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  • 舌上皮性異形成および上皮内癌と診断された病変の診断および治療の検討

    新美 奏恵, 船山 昭典, 丸山 智, 勝良 剛詞, 新國 農, 田沼 順一, 林 孝文, 小林 正治

    日本口腔診断学会雑誌   33 ( 1 )   126 - 126   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • 下顎骨内に発生した類皮嚢胞の1例

    笠原 映, 山崎 学, 丸山 智, 勝良 剛詞, 黒川 亮, 河原田 壮史, 林 孝文, 高木 律男, 田沼 順一

    日本口腔診断学会雑誌   33 ( 1 )   139 - 139   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • 舌腫瘍

    河原田 壮史, 丸山 智, 笠原 映, 山崎 学, 林 孝文, 片桐 渉, 小林 正治, 田沼 順一

    日本口腔診断学会雑誌   33 ( 1 )   81 - 81   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔診断学会  

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  • 唾液腺多形腺腫における低酸素応答性増殖機構(Hypoxia-induced proliferation in salivary pleomorphic adenoma cells)

    丸山 智, 山崎 学, 田沼 順一

    日本癌学会総会記事   78回   P - 2282   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 癌関連線維芽細胞はSOX9を高発現させ口腔癌細胞の遊走および浸潤を促進する(Cancer-associated fibroblasts promote the migration and invasion of oral cancer cells via enhancing SOX9 expression)

    羽賀 健太, 山崎 学, 丸山 智, 小林 正治, 田沼 順一

    日本癌学会総会記事   78回   P - 1258   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • PET-CT検査における口腔癌の頸部リンパ節転移の診断精度に関する検討

    新垣 元基, 勝見 祐二, 小山 貴寛, 永田 昌毅, 星名 秀行, 高村 真貴, 林 孝文, 丸山 智, 田沼 順一, 高木 律男

    日本口腔科学会雑誌   68 ( 2 )   111 - 111   2019年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • 下顎角部に発生した奇形様嚢胞の1例

    齋藤 大輔, 原 太一, 丸山 智, 西山 秀昌, 林 孝文, 小林 正治

    日本口腔外科学会雑誌   65 ( 7 )   479 - 483   2019年7月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

    症例は17歳女性で、8歳頃に発熱した際に左側下顎角部の腫脹を認め、解熱後も残存していたが放置していた。14歳ごろから徐々に増大を自覚しており当科を紹介受診した。画像所見から脂肪腫または類皮嚢胞と診断し、全身麻酔下で経皮的に病変の摘出術を施行した。病変は耳下腺下極の内側に入り込んでおり、周囲耳下腺組織からの剥離は一部でやや困難であったが一塊として摘出した。術後6年6ヵ月間経過観察を行っていたが、再発所見を認めないため経過観察を終了とした。病理組織学的所見では大小2個の嚢胞腔を認め、いずれの嚢胞も内腔面は皮膚表皮様の基底線の平坦な重層扁平上皮で被覆されており、線維性組織から成る難胞壁はおおむね薄く、二つの嚢胞間部は肥厚していた。奇形様嚢胞との病理組織学的診断を下した。

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  • 放射線誘発が疑われた口腔内多発癌の1例

    三上 俊彦, 船山 昭典, 金丸 祥平, 新美 奏恵, 丸山 智, 小林 正治

    日本口腔内科学会雑誌   25 ( 1 )   10 - 15   2019年6月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔内科学会  

    患者は60歳の女性で、右側上顎の疼痛を主訴に受診した。当科受診7年前に他院で左側舌縁部扁平上皮癌の診断で舌部分切除術と術後放射線治療を受けていた。当科初診時、右側上顎、左側頬粘膜、下顎唇側歯肉に腫瘍性病変を認め、生検の結果3部位とも扁平上皮癌の診断であった。右側上顎骨部分切除術、左側頬粘膜部腫瘍切除術および下顎骨辺縁切除術を施行したが、原発巣の再発と頸部転移を認め、制御不能となり当科における初回手術から3年後に永眠された。(著者抄録)

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  • 臓器病理学の最近の進歩 頭頸部腫瘍病理学の最先端 口腔上皮性腫瘍の病理学的考察 口腔の前癌病変と早期癌に関する問題点

    田沼 順一, 山崎 学, 丸山 智

    日本病理学会会誌   108 ( 1 )   226 - 226   2019年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 高分子ゲル音響カップリング材を併用した舌癌の口腔内超音波検査による深達度計測

    林 孝文, 曽我 麻里恵, 小林 太一, 高村 真貴, 新國 農, 勝良 剛詞, 丸山 智, 田沼 順一

    超音波医学   46 ( Suppl. )   S788 - S788   2019年4月

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    記述言語:日本語   出版者・発行元:(公社)日本超音波医学会  

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  • LADININ-1 IS INVOLVED IN CELL MOTILITY AND PROLIFERATION OF ORAL SQUAMOUS CELL CARCINOMA CELLS (proceeding)

    阿部 達也

    128 ( 1 )   e81 - e82   2019年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)  

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  • PET‐CT検査における口腔癌の頸部リンパ節転移の診断精度に関する検討

    新垣元基, 勝見祐二, 小山貴寛, 永田昌毅, 星名秀行, 高村真貴, 林孝文, 丸山智, 田沼順一, 高木律男

    日本口腔科学会学術集会プログラム・抄録集   73rd   157   2019年

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    記述言語:日本語  

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  • 舌扁平上皮癌cN0症例の頸部後発転移に関する検討

    小玉直樹, 永田昌毅, 小山貴寛, 勝見祐二, 新垣元基, 木口哲郎, 原夕子, 池田順行, 児玉泰光, 星名秀行, 西山秀昌, 林孝文, 丸山智, 田沼順一, 高木律男

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   37th   185   2019年

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  • アクチン分子を介した ladinin-1 の口腔扁平上皮癌細胞増殖・遊走制御機 構

    阿部達也, 味岡洋一, 山崎学, 丸山智

    日本病理学会会誌   108 ( 1 )   323 - 323   2019年

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)  

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  • 口蓋に生じた唾液腺導管癌の一例

    山崎学, 丸山智, 常木雅之, 田沼順一, 田沼順一

    日本臨床細胞学会雑誌(Web)   57   647   2018年10月

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  • 口蓋に生じた唾液腺導管癌の一例

    山崎 学, 丸山 智, 常木 雅之, 田沼 順一

    日本臨床細胞学会雑誌   57 ( Suppl.2 )   647 - 647   2018年10月

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    記述言語:日本語   出版者・発行元:(公社)日本臨床細胞学会  

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  • 口腔扁平上皮癌における死細胞誘導性細胞増殖機構の解明

    山崎 学, 丸山 智, 阿部 達也, 田沼 順一

    日本病理学会会誌   107 ( 1 )   346 - 346   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔粘膜悪性境界病変におけるp53免疫組織化学的検索の取り組み

    丸山 智, 山崎 学, 阿部 達也, 田沼 順一

    日本病理学会会誌   107 ( 1 )   459 - 459   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌細胞におけるladinin-1の機能解析

    阿部 達也, 丸山 智, 山崎 学, 味岡 洋一

    日本病理学会会誌   107 ( 1 )   458 - 458   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔粘膜悪性境界病変におけるp53免疫組織化学的検索の取り組み

    丸山 智, 山崎 学, 阿部 達也, 田沼 順一

    日本病理学会会誌   107 ( 1 )   459 - 459   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌における死細胞誘導性細胞増殖機構の解明

    山崎 学, 丸山 智, 阿部 達也, 田沼 順一

    日本病理学会会誌   107 ( 1 )   346 - 346   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 舌扁平上皮癌における「厚み」の臨床病理学的検討

    三上俊彦, 金丸祥平, 千田正, 船山昭典, 小田陽平, 新美奏恵, 丸山智, 林孝文, 小林正治

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   36th   204   2018年

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  • Ladinin-1 はアクチン分子動態の調整を介し、口腔扁平上皮癌細胞の増殖と遊走を制御する

    阿部達也, 山崎学, 丸山智, 味岡洋一

    第29回日本臨床口腔病理学会総会・学術大会 プログラム・抄録集   86 - 86   2018年

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    掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)  

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  • 口腔扁平上皮癌におけるSOX 9細胞質発現は予後不良と関連する

    隅田 賢正, 山崎 学, 阿部 達也, 高木 律男, 丸山 智

    新潟歯学会雑誌   47 ( 2 )   120 - 121   2017年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 下顎部に発生したInfantile Fibromatosisの1例

    小玉 直樹, 高山 裕司, 永田 昌毅, 小山 貴寛, 勝見 祐二, 新垣 元基, 隅田 賢正, 池田 順行, 大貫 尚志, 齋藤 太郎, 山田 瑛子, 西山 秀昌, 林 孝文, 丸山 智, 高木 律男

    小児口腔外科   27 ( 2 )   68 - 68   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本小児口腔外科学会  

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  • 感染性リンパ節腫脹との鑑別に苦慮した悪性リンパ腫の1例

    三上 俊彦, 原 太一, 加藤 祐介, 船山 昭典, 金丸 祥平, 小田 陽平, 新美 奏恵, 阿部 達也, 丸山 智, 西山 秀昌, 林 孝文, 小林 正治

    日本口腔科学会雑誌   66 ( 2 )   182 - 182   2017年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • Expression of neprilysin in periodontitis-affected gingival tissues

    A. Nezu, T. Kubota, S. Maruyama, M. Nagata, K. Nohno, T. Morozumi, H. Yoshie

    ARCHIVES OF ORAL BIOLOGY   79   35 - 41   2017年7月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Objective: Although the pathogeneses of Alzheimer's disease (AD) and periodontal diseases have overlapping features, including ageing and chronic inflammation, the association between AD and periodontitis remains unclear. To explore the pathogenesis of periodontitis, a comprehensive gene expression/transcriptome analysis in periodontitis-affected gingival tissues found that the AD pathway was significantly up-regulated in periodontitis-affected gingival tissues. AD-related genes, amyloid beta precursor protein (APP), interleukin-1 beta and compliment 1QA, were significantly elevated in periodontitis. In the present study, balance between mRNA expression of APP and a potent amyloid degradation enzyme, neprilysin (NEP), as well as protein localisation of APP and NEP were analysed.
    Design: Eighteen periodontitis-affected and 18 clinically healthy control gingival tissues were taken from patients with severe chronic periodontitis or undergoing tooth extraction. Total RNA was purified and used for quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR). The localisation of APP and NEP was analysed by immunohistochemistry (IHC).
    Results: Both APP and NEP genes were up-regulated in periodontitis-affected gingival tissues. APP expressing macrophages and NEP-expressing neutrophils and fibroblasts, reflecting inflammatory stages, were detected in inflamed gingival tissues by IHC.
    Conclusion: The up-regulation of APP and NEP mRNA levels in periodontitis-affected gingival tissues compared with healthy controls was confirmed by qRT-PCR analyses. Since NEP is one of the primary enzymes that degrades amyloid beta, increased NEP mRNA levels in periodontitis may act as an inhibitor of amyloid beta accumulation in gingival tissues, balancing increased APP mRNA expression. However, NEP has several effects including degradation of vasoactive substances; therefore, further sresearch is needed. (C) 2017 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.archoralbio.2017.03.003

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  • 低酸素環境下でMYCは唾液腺多形性腺腫由来細胞の生存・増殖を亢進する

    丸山 智, 山崎 学, 阿部 達也, 隅田 賢正, 程 クン, 朔 敬

    日本病理学会会誌   106 ( 1 )   295 - 295   2017年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌におけるSOX9の発現様式

    隅田 賢正, 丸山 智, 山崎 学, 阿部 達也, 高木 律男, 程 クン

    日本病理学会会誌   106 ( 1 )   364 - 364   2017年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔表在性癌と非癌部粘膜上皮との界面におけるタンパク質動態解析

    阿部 達也, 丸山 智, 山崎 学, 許 波, 隅田 賢正, 程 クン, 山本 格, 朔 敬

    日本病理学会会誌   106 ( 1 )   408 - 408   2017年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔癌治療後に生じたbizarre stromal reactionの2例

    山崎 学, 隅田 賢正, 丸山 智, 阿部 達也, 程 くん, 朔 敬

    日本病理学会会誌   106 ( 1 )   424 - 424   2017年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 前舌腺に発生した腺癌NOSの1例

    三上俊彦, 船山昭典, 金丸祥平, 小田陽平, 山崎学, 丸山智, 西山秀昌, 林孝文, 小林正治

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   35th   174   2017年

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  • 歯周炎罹患歯肉組織におけるネプリライシンの遺伝子発現レベルと免疫組織局在の解析

    根津新, 久保田健彦, 丸山智, 永田昌毅, 堀水慎, 濃野要, 保苅崇大, 両角俊哉, 朔敬, 吉江弘正

    新潟歯学会雑誌   46 ( 2 )   115   2016年12月

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  • 新潟大学医歯学総合病院顎顔面口腔外科における口腔扁平苔癬患者の臨床統計的検討

    齋藤 太郎, 小山 貴寛, 黒川 亮, 西川 敦, 原 夕子, 清水 志保, 丸山 智, 程 君, 高木 律男

    新潟歯学会雑誌   46 ( 2 )   119 - 120   2016年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 口腔表在性癌と非癌部粘膜上皮との界面における細胞競合現象の解析

    阿部 達也, 丸山 智, 山崎 学, 許 波, Babkair Hamzah, 隅田 賢正, 程 君, 山本 格, 朔 敬

    日本病理学会会誌   105 ( 1 )   421 - 421   2016年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔粘膜乳頭腫は粘液腺導管開口部に発生する

    朔 敬, 丸山 智, 山崎 学, 阿部 達也, バブカイール・ハムザ, 隅田 賢正, 程 君

    日本病理学会会誌   105 ( 1 )   419 - 419   2016年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 唾液腺多形性腺腫細胞は低酸素環境下でHIF-1α-MYC相互作用によってエネルギー代謝を制御している

    丸山 智, 山崎 学, 阿部 達也, バブカイール・ハムザ, 隅田 賢正, 程 君, 朔 敬

    日本病理学会会誌   105 ( 1 )   468 - 468   2016年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 発生学的組織病理形成ではなく炎症により生じた口腔内リンパ管上皮嚢胞(Inflammatory but not developmental histopathogenesis of intraoral lymphoepithelial cyst)

    山崎 学, 丸山 智, 阿部 達也, バブカイール・ハムザ, 隅田 賢正, 程 君, 朔 敬

    日本病理学会会誌   105 ( 1 )   424 - 424   2016年4月

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    記述言語:英語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌における皮膚型角化の分化誘導と細胞増殖の調整機構

    阿部 達也, 丸山 智, 山崎 学, Babkair Hamzah, 隅田 賢正, 程 くん, 朔 敬

    新潟歯学会雑誌   45 ( 2 )   103 - 103   2015年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 口腔表在性癌と非癌部粘膜上皮との界面における細胞競合現象

    阿部 達也, 丸山 智, 山崎 学, Babkair Hamzah, 隅田 賢正, 程 くん, 朔 敬

    新潟歯学会雑誌   45 ( 2 )   105 - 106   2015年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 歯周炎罹患歯肉組織におけるNeprilysin(Alzheimer病関連遺伝子)の発現

    根津新, 久保田健彦, 丸山智, 永田昌毅, 堀水慎, 濃野要, 保苅崇大, 両角俊哉, 朔敬, 吉江弘正

    日本歯周病学会会誌(Web)   57   131   2015年8月

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  • PROTEASE-ACTIVATED RECEPTOR-2 IN REGULATION OF PROLIFERATION AND INVASION OF ORAL SQUAMOUS CELL CARCINOMA CELLS

    J. Cheng, K. Al-Eryani, T. Abe, S. Maruyama, M. Yamazaki, H. Babkair, T. Saku

    EUROPEAN JOURNAL OF CANCER   51   E12 - E13   2015年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCI LTD  

    DOI: 10.1016/j.ejca.2015.06.039

    Web of Science

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  • 角化嚢胞性歯原性腫瘍の組織学的バリエーションの検討 炎症性修飾を中心に

    山崎 学, 丸山 智, 阿部 達也, 程 くん, 酒井 剛, 朔 敬

    日本病理学会会誌   104 ( 1 )   469 - 469   2015年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 低酸素応答性ファイブロネクチン生合成が唾液腺多形性腺腫由来SM-AP細胞の増殖を促進する

    丸山 智, 山崎 学, 阿部 達也, バブカイル・ハムザ, 程 くん, 朔 敬

    日本病理学会会誌   104 ( 1 )   449 - 449   2015年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌および正角化型異型上皮における正角化関連分子の動態

    阿部 達也, 丸山 智, 山崎 学, バブカイル・ハムザ, 程 くん, 朔 敬

    日本病理学会会誌   104 ( 1 )   467 - 467   2015年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 腺様嚢胞癌細胞の転移 KGFシグナルによる細胞増殖性と遊走性の相反的制御機構

    丸山 智, 山崎 学, 阿部 達也, 程 クン, 朔 敬

    日本口腔科学会雑誌   63 ( 4 )   435 - 436   2014年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • 口腔扁平上皮癌においてMFG-E8は同種死細胞処理だけでなく腫瘍進展にも関与している

    山崎 学, 程 クン, 丸山 智, 阿部 達也, 朔 敬

    日本口腔科学会雑誌   63 ( 4 )   387 - 387   2014年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • 角化嚢胞性歯原性腫瘍は咀嚼筋内にも発生する 角化性嚢胞の免疫組織化学的鑑別法

    阿部 達也, 丸山 智, 山崎 学, ハムザ・バブカイル, 三上 俊彦, 新垣 晋, 小林 正治, 林 孝文, 程 クン, 朔 敬

    日本口腔科学会雑誌   63 ( 4 )   414 - 415   2014年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • 口腔異型上皮-扁平上皮癌シーケンスにおける正角化関連分子の発現動態

    阿部 達也, 丸山 智, Ahmed Essa, Hamzah Babkair, 山崎 学, 程 くん, 朔 敬

    日本病理学会会誌   103 ( 1 )   281 - 281   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌における接着結合分子のclaudin 1とzonula occludens 1(Tight junction molecules, claudin 1 and zonula occludens 1, in oral squamous cell carcinoma)

    Hamzah Babkair, 山崎 学, 阿部 達也, Ahmed Essa, 丸山 智, 程 くん, 朔 敬

    日本病理学会会誌   103 ( 1 )   281 - 281   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌細胞におけるMFG-E8発現の意義 過剰発現細胞系による解析

    山崎 学, 程 くん, 丸山 智, 阿部 達也, 朔 敬

    日本病理学会会誌   103 ( 1 )   295 - 295   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 唾液腺多形性腺腫由来SM-AP細胞の増殖は低酸素応答性パールカン生合成に依存している

    丸山 智, 山崎 学, 阿部 達也, Babkair Hamzah, 程 くん, 朔 敬

    日本病理学会会誌   103 ( 1 )   296 - 296   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 唾液腺腫瘍の新規筋上皮細胞マーカとしてのコネキシン43とpodoplanin(Connexin 43 and podoplanin as novel myoepithelial cell markers in salivary gland tumors)

    Ahmed Essa, 常木 雅之, 山崎 学, 丸山 智, 阿部 達也, Hamzah Babkair, 程 くん, 朔 敬

    日本病理学会会誌   103 ( 1 )   273 - 273   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本病理学会  

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  • Amyloid beta (A4) precursor protein expression in human periodontitis-affected gingival tissues

    T. Kubota, T. Kubota, S. Maruyama, D. Abe, T. Tomita, T. Morozumi, N. Nakasone, T. Saku, T. Saku, H. Yoshie

    Archives of Oral Biology   59   586 - 594   2014年1月

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    Objective Periodontitis involves periodontal tissue destruction and is associated with chronic inflammation and ageing. Periodontitis has recently been recognised as a risk factor for Alzheimer&#039;s disease (AD). We showed upregulation of molecules in the AD pathway including amyloid beta (A4) precursor protein (APP), a key gene in AD, interleukin-1 beta (IL-1β), and complement component 1 (q subcomponent, A chain) (C1QA) in periodontitis compared to healthy tissues. Here, we quantitatively analysed the expression levels of APP, IL-1β, and C1QA and determined the localisation of APP in gingival tissues. Design Fourteen chronic periodontitis patients and 14 healthy participants were enrolled. Six samples of total RNA from two distinct sites of healthy and periodontitis-affected gingival tissues from three randomly selected patients were used for microarray analyses, and significant biological pathways in periodontitis were identified. Differential gene expression of APP, IL-1β, and C1QA, which belong to the AD pathway, were analysed with quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR) using samples from these 14 chronic periodontitis patients and 14 healthy controls. APP localisation was analysed with immunohistochemistry. Results APP, IL-1β, and C1QA mRNA levels were significantly upregulated in periodontitis-affected gingival tissues. APP was mainly localised in macrophages in gingival connective tissues underneath the epithelial layers. Conclusions An association between AD and periodontitis was detected with microarray and computer-aided data mining analyses. qRT-PCR identified differential gene expression in periodontitis-affected gingival tissue that may be related to AD pathogenesis. Elevated APP, IL-1β, and C1QA transcripts and APP-expressing macrophages in periodontitis-affected gingival tissues were observed, suggesting a relationship between periodontitis and AD pathogenesis. © 2014 Elsevier Ltd.

    DOI: 10.1016/j.archoralbio.2014.03.004

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  • 当科における過去10年間の口腔がん患者の臨床的検討

    三上俊彦, 船山昭典, 芳澤享子, 新垣晋, 林孝文, 丸山智, 朔敬, 小林正治

    新潟歯学会雑誌   43 ( 2 )   163 - 164   2013年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 口腔扁平上皮癌とその境界病変における術中迅速病理診断の意義 局所再発に関する臨床病理学的検討

    御代田 駿, 小林 孝憲, 宮島 久, 永田 昌毅, 星名 秀行, 小林 正治, 高木 律男, 丸山 智, 朔 敬

    新潟歯学会雑誌   43 ( 2 )   163 - 163   2013年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • MFG-E8は口腔扁平上皮癌の進展と死細胞貪食を促進する

    山崎 学, 程 くん, 丸山 智, 阿部 達也, 朔 敬

    日本病理学会会誌   102 ( 1 )   360 - 360   2013年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌の側方進展界面における細胞死

    阿部 達也, 丸山 智, Ahmed Essa, Hamzah Babkair, 山崎 学, 程 くん, 朔 敬

    日本病理学会会誌   102 ( 1 )   319 - 319   2013年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌における間質性マクロファージ(Stromal macrophages in oral squamous cell carcinoma)

    Ahmed Essa, 山崎 学, 丸山 智, 阿部 達也, Hamzah Babkair, 程 くん, 朔 敬

    日本病理学会会誌   102 ( 1 )   361 - 361   2013年4月

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    記述言語:英語   出版者・発行元:(一社)日本病理学会  

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  • 唾液腺多形性腺腫細胞における低酸素応答性の細胞外基質合成

    丸山 智, 山崎 学, 阿部 達也, 程 くん, 朔 敬

    日本病理学会会誌   102 ( 1 )   364 - 364   2013年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔扁平上皮癌・上皮内癌の側方進展界面の病理組織学的解析(Histopathological varieties of lateral invasion fronts in oral squamous cell carcinoma and carcinoma in-situ)

    阿部 達也, 丸山 智, 山崎 学, アーメッド・イーサー, 程 ジュン, 朔 敬

    日本癌学会総会記事   71回   144 - 145   2012年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 口腔扁平上皮癌の浸潤を契機とした細胞外基質産生の実質細胞から間質細胞へのスイッチング機構(Parenchymal-stromal switching for extracellular matrix production before/after invasion of oral squamous cell carcinoma)

    丸山 智, 山崎 学, 阿部 達也, 程 ジュン, 朔 敬

    日本癌学会総会記事   71回   144 - 144   2012年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Sialadenitis as a possible risk factor for salivary gland cancer

    M. Hasegawa, J. Cheng, S. Maruyama, M. Yamazaki, T. Saku

    INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   40 ( 12 )   1449 - 1450   2011年12月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:CHURCHILL LIVINGSTONE  

    DOI: 10.1016/j.ijom.2011.06.022

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  • Podoplanin Regulates the Proliferation of Oral Squamous Cell Carcinoma Cells via Its Binding to Extracellular Matrix

    M. Tsuneki, S. Maruyama, M. Yamazaki, J. Cheng, T. Saku

    EUROPEAN JOURNAL OF CANCER   47   S550 - S550   2011年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCI LTD  

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  • 顎下腺内側のリンパ節【傍顎下腺リンパ節】転移と考えられる舌癌4症例の画像診断学的検討

    星名 由紀子, 林 孝文, 新垣 晋, 齊藤 力, 星名 秀行, 高木 律男, 丸山 智

    頭頸部癌   36 ( 2 )   186 - 186   2010年5月

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    記述言語:日本語   出版者・発行元:(一社)日本頭頸部癌学会  

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  • ビスフォスフォネート製剤による顎骨壊死の病理組織学的検討

    長谷川 真弓, 程 くん, 丸山 智, 小林 孝憲, 又賀 泉, 田中 彰, 岡田 康男, 田上 正, 小松 繁樹, 泉 直也, 齊藤 力, 高木 律男, 田中 礼, 林 孝文, 朔 敬

    日本口腔科学会雑誌   58 ( 4 )   199 - 199   2009年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本口腔科学会  

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  • Hemophagocytosis-related keratinization in squamous cell carcinoma and carcinoma in-situ of the oral mucosa

    K. Al-Eryani, J. Cheng, S. Maruyama, M. Yamazaki, T. Kobayashi, T. Saku

    EJC SUPPLEMENTS   7 ( 2 )   481 - 481   2009年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

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  • 脈管分布様式からみたワルチン腫瘍のリンパ性間質

    阿部 達也, 程 くん, 丸山 智, 朔 敬

    日本病理学会会誌   98 ( 1 )   398 - 398   2009年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • CK17と14‐3‐3σの共発現が口腔粘膜扁平上皮癌で強調される

    三上俊彦, CHENG Jun, 丸山智, 小林孝憲, 依田浩子, 新垣晋, 齊藤力, 朔敬

    日本臨床口腔病理学会総会・学術大会プログラム・抄録集   19th   69   2008年8月

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    記述言語:日本語  

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  • 口腔粘膜扁平上皮癌・上皮内癌の再発に関する臨床病理学的検討

    小林 孝憲, 依田 浩子, 丸山 智, 程 くん, 齊藤 力, 高木 律男, 朔 敬

    日本病理学会会誌   97 ( 1 )   320 - 320   2008年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔粘膜悪性境界病変におけるケラチン分子とその関連因子

    三上俊彦, 程くん, 丸山智, 新垣晋, 齊藤力, 朔敬

    新潟歯学会雑誌   37 ( 2 )   257 - 257   2007年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 口腔扁平上皮癌のいわゆる癌真珠の免疫組織学的検討

    三上俊彦, CHENG J, 丸山智, AL‐ERYANI K, 新垣晋, 齊藤力, 朔敬

    J Oral Biosci   49 ( Supplement )   132 - 132   2007年8月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • 第三大臼歯に関連した下顎第二大臼歯の重篤な歯根吸収

    飯田 明彦, 高木 律男, 丸山 智, 朔 敬, ホワイト・レイモンド

    日本口腔外科学会雑誌   53 ( Suppl. )   181 - 181   2007年8月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

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  • 口腔粘膜上皮内癌の鑑別診断にはCK17の免疫組織化学が有用である

    三上俊彦, 程くん, 船山昭典, 丸山智, スカリアン クンドゥ, スカリアン クンドゥ, 新垣晋, 齊藤力, 朔敬

    日本病理学会会誌   96 ( 1 )   291 - 291   2007年2月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • Periosteal osteosarcoma of the jawbones: a clinicopathological review

    Sawair FA, Cheng J, Hao N, Maruyama S, Hoshina H, Takagi R, Koyama J, Hayashi T, Saku T

    Oral Med Pathol   12 ( 1 )   3 - 10   2007年

  • 第三大臼歯に関連した歯根吸収により抜歯にいたった下顎第二大臼歯の2症例

    飯田明彦, 高木律男, 丸山智, 朔敬, 齋藤功

    新潟歯学会雑誌   36 ( 2 )   303   2006年12月

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    記述言語:日本語  

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  • [第29回]上顎悪性神経鞘腫

    丸山 智, 中里 隆之, 小山 純市, 鈴木 誠

    新潟歯学会雑誌   36 ( 2 )   31 - 34   2006年12月

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    記述言語:日本語   出版者・発行元:新潟大学  

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    その他リンク: http://hdl.handle.net/10191/1343

  • 口腔粘膜上皮悪性境界病変におけるいわゆる幹細胞マーカ分子の発現様式

    小林 孝憲, 依田 浩子, 船山 昭典, 丸山 智, 程 君, 高木 律男, 朔 敬

    日本病理学会会誌   95 ( 1 )   288 - 288   2006年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 口腔粘膜悪性境界病変の病理組織学的診断根拠としての機能性分子発現様式の解析

    小林 孝憲, 依田 浩子, 丸山 智, 程 くん, 高木 律男, 朔 敬

    新潟歯学会雑誌   35 ( 2 )   247 - 247   2006年1月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 上顎悪性神経鞘腫

    丸山 智, 中里隆之, 小山純市, 鈴木 誠

    新潟歯学会雑誌   36 ( 2 )   239 - 42   2006年

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  • 歯原性角化嚢胞モデルとしてのMsx2ノックアウトマウス顎骨嚢胞

    朔 敬, 板垣 真奈美, 依田 浩子, 丸山 智, 程 君, 大島 勇人, 里方 一郎

    Journal of Oral Biosciences   47 ( Suppl. )   96 - 96   2005年9月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • Integrin alpha is indispensable for ligaments to resist mechanical stress-induced mineralization.

    F Takizawa, T Yoshizawa, S Maruyama, F Iizawa, A Matsuda, O Ishibashi, T Saku, H Yoshie, U Mayer, H Kawashima

    JOURNAL OF BONE AND MINERAL RESEARCH   20 ( 9 )   S109 - S110   2005年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC BONE & MINERAL RES  

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  • 唾液腺多形性腺腫内癌腫発生モデル細胞系の樹立とその特性

    丸山 智, 程 [クン], 新垣 晋[他]

    新潟歯学会雑誌   35 ( 1 )   73 - 74   2005年7月

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    記述言語:日本語   出版者・発行元:新潟大学  

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  • 石灰化歯原性嚢胞上皮細胞の幻影細胞化と石灰化機序の検討

    程 君, 丸山 智, 鈴木 誠, 藤田 一, 高木 律男, 草間 薫, 朔 敬

    日本病理学会会誌   94 ( 1 )   252 - 252   2005年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

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  • 石灰化歯原性嚢胞上皮細胞 : 染色体解析と移植腫瘍石灰化機序の検討

    程 王君., 丸山 智, 鈴木 誠, 下川 仁弥太, 朔 敬.

    歯科基礎医学会雑誌   45 ( 5 )   317 - 317   2003年9月

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    記述言語:日本語   出版者・発行元:歯科基礎医学会  

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  • 唾液腺多形性腺腫腫由来細胞PMA1-PMA6による細胞外基質生合成

    丸山 智, 程 君, 朔 敬

    歯科基礎医学会雑誌   45 ( 5 )   359 - 359   2003年9月

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    記述言語:日本語   出版者・発行元:歯科基礎医学会  

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  • Carcinoma in-situ of the oral mucosa has a definite tendency towards keratinization

    Syafriadi M, Ida-Yonemochi H, Ikarashi T, Maruyama S, Jen KY, Cheng J, Hoshina H, Takagi R, Saku T

    Oral Med Pathol   8 ( 2 )   43 - 44   2003年

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

    A 81-year-old female had suffered from a white lesion in the right lateral margin of the tongue for 10 years. The lesions was surgically removed and examined histopathologically. The surgical specimen showed small foci of squamous cell carcinoma invading up to 4 mm in the muscle layer with a diameter of less than 7 mm in the central portion. The carcinomatous foci were surrounded by epithelial dysplasia in various degrees with a dense lymphocytic infiltration in the lamina propriae. Some of the dysplasia parts just next to the carcinomatous foci contained obviously atypical cells without basal cell alignment but with an apparent keratinizing tendency, which could not be otherwise diagnosed as carcinoma in-situ. Based on this case report, a new concept of carcinoma in-situ of the oral mucosa was proposed, because the histology was different in terms of keratinization degree from so-called carcinoma in-situ as frequently seen in the cervix uteri, which were mainly composed of proliferation of basaloid cells.

    DOI: 10.3353/omp.8.43

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    その他リンク: http://search.jamas.or.jp/link/ui/2004123235

  • 40. Tumor of the upper lip

    Maruyama S, Cheng J, Ikarashi T, Hoshina H, Takagi R, Saku T

    Oral medicine & pathology   7 ( 2 )   98 - 98   2002年12月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

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  • 20. White lesion of the oral mucosa

    Syafriadi M, Ida H, Ikarashi I, Maruyama S, Jen KY, Cheng J, Hoshina H, Takagi R, Saku T

    Oral medicine & pathology   7 ( 2 )   94 - 94   2002年12月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

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  • 石灰化歯原性嚢胞5例の臨床病理学的検討

    奈良井 省太, 福田 純一, 高木 律男, 小野 和宏, 星名 秀行, 藤田 一, 長島 克弘, 平 周三, 丸山 智, 朔 敬

    新潟歯学会雑誌   32 ( 2 )   355 - 356   2002年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 石灰化歯原性嚢胞上皮細胞の試験管内石灰化と幻影細胞化

    程 くん, 丸山 智, 鈴木 誠, 藤田 一, 高木 律男, 朔 敬

    歯科基礎医学会雑誌   44 ( 5 )   480 - 480   2002年9月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • Mucoepidermoid Carcinoma in Children : Report of a case and review of literature

    Jen Kai Yu, Cheng Jun, Maruyama Satoshi, Hayashi Takafumi, Suzuki Ichiro, Shingaki Susumu, Saku Takashi

    Oral medicine & pathology   7 ( 1 )   27 - 31   2002年6月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

    A rare case of mucoepidermoid carcinoma arising in a 15-year-old boy is reported. The patient had palatal swelling with tenderness for two years. After a diagnosis of mucoepidermoid carcinoma was obtained by biopsy and CT scan examinations, the patient underwent a partial maxillectomy. Histopathologically, the tumor arising in the palatal mucosa involved the maxillary bone and the base of the right maxillary sinus. The tumor consisted not only of predominantly clear cells and squamous cells in solid nests but also of mucous cells forming various sized cystic cavities. From a review of the literature, mucoepidermoid carcinoma was shown to be the most frequent salivary tumor in children, comprising 3% to 8% of the total numbers of patients with mucoepidermoid carcinoma. When compared with adult cases, childhood cases more frequently involve the parotid gland and less frequently the minor salivary glands.

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  • 舌癌—舌癌と胃癌が重複した1例—

    丸山 智, 林 孝文, 川上美貴

    新潟歯学会雑誌   32 ( 1 )   79 - 82   2002年

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  • 11.Mucoepidermoid carcinoma of children : report of a case and literature review

    Jen KY, Cheng J, Maruyama S, Suzuki I, Shingaki S, Saku T

    Oral medicine & pathology   6 ( 2 )   111 - 111   2001年12月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

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  • 24.Tumor of the maxilla

    Maruyama S, Cheng J, Suzuki M, Sohma Y, Takagi R, Saku T

    Oral medicine & pathology   6 ( 2 )   114 - 114   2001年12月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

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  • 23.Tumor of the mandible

    Igarashi T, Maruyama S, Hoshina H, Takagi R, Saku T

    Oral medicine & pathology   6 ( 2 )   113 - 114   2001年12月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

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  • 疣贅型黄色腫10例の検討

    加納 浩之, 小林 正治, 新垣 晋, 飯田 明彦, 高木 律男, 丸山 智, 朔 敬

    日本口腔外科学会雑誌   47 ( 13 )   1060 - 1060   2001年12月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

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  • 23:Submucosal tumor of the buccal mucosa

    Maruyama S, Hao N, Cheng J, Horino K, Saku T

    Oral medicine & pathology   5 ( 2 )   122 - 122   2000年12月

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    記述言語:英語   出版者・発行元:特定非営利活動法人日本臨床口腔病理学会  

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  • 唾液腺多形性腺腫の被膜浸潤

    丸山 智, 朔 敬, 程 君, 鈴木 誠

    歯科基礎医学会雑誌   42 ( 5 )   436 - 436   2000年8月

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    記述言語:日本語   出版者・発行元:歯科基礎医学会  

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▶ 全件表示

共同研究・競争的資金等の研究

  • 細胞外基質環境下における腫瘍特異的なCD73誘導低酸素応答性増殖機構の解明

    研究課題/領域番号:21K10109

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    丸山 智, 阿部 達也, 山崎 学, 田沼 順一

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    1) CD73発現抑制によるECMの発現動態の検証: 低酸素環境下におけるCD73発現とECM合成能との関係を解析するために、siRNA法によるCD73発現抑制下でのECM分子である、perlecanやfibronectinの発現を検討したところ、SM-AP1/4ともに発現抑制はみられなかった。よってCD73発現はECM合成能に影響を及ぼしていない可能性が示唆された。
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    2) 細胞増殖関連液性因子の網羅的解析: SM-AP細胞を低酸素培養条件下と通常培養条件下及びsiRNA法によるCD73発現抑制下で培養した後、各培養上清を回収し、Proteome ProfilerTM 抗体アレイキット(R&D systems)を用いて細胞増殖関連液性因子の網羅的解析を行った。その結果、IP-10やAngiogeninなどCD73発現抑制下で同様に発現が抑制されるいくつかの候補分子を見出した。さらにこれまでの研究で、これらの候補分子は低酸素培養条件(1%O2/5%CO2/94%N2)及び通常培養条件下でのSM-AP細胞系における各培養上清において発現が亢進していることもわかっており、低酸素下において、HIF-1αを介したCD73発現上昇との関連も確認されている。
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    3) CD73発現動態におけるSTAT3の影響についての検討: 昨年度に続いて、siRNA法によるCD73及びHIF-1α発現抑制下でのSTAT3の発現を比較してみると、SM-AP1/4ともにCD73抑制下では、STAT3の発現抑制傾向が見られたものの、HIF-1α発現抑制下ではSTAT3の発現抑制はみられなかった。以上の結果からは、低酸素下において、HIF-1αを介さない別の経路でSTAT3の発現上昇をきたしている可能性が示唆された。

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  • 死細胞貪食による口腔がん細胞活性化:脂質クオリティが果たす役割を探る

    研究課題/領域番号:21K09856

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    山崎 学, 阿部 達也, 丸山 智, 冨原 圭, 泉 健次, 田沼 順一

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    がん細胞は正常細胞とは異なる脂質代謝を有し、近年、がんにおける脂質クオリティ(脂質組成)の重要性が明らかになりつつある。本研究課題では、「死細胞貪食を起点としたがん細胞活性化の機序に、死細胞由来脂質によってもたらされる脂質クオリティ変化が関与する」という仮説のもと、(1)がん細胞のおける死細胞由来脂質の局在変化を追跡し、(2)貪食後に生じるがん細胞の脂質クオリティを解析することで、(3)細胞増殖・遊走・浸潤能に関わる分子機構との接点を明らかにすることを目的としている。今年度は、以下の疑問を解決すべく検討をおこなった。
    1) ネクローシス細胞は生活がん細胞に貪食されるのか?: 口腔扁平上皮癌由来培養細胞株を脂質親和性色素PKH26にて標識後、凍結融解によって誘導したネクローシス細胞を、同種の生活がん細胞と共培養した。共焦点レーザー顕微鏡解析の結果、PKH26陽性を示す死細胞断片は生活がん細胞の細胞質内に認められた。これより、ネクローシス細胞は生活がん細胞によって貪食されることが示された。
    2) 細胞内コレステロール変化は細胞機能を変化させるのか?: これまでの検討により、ネクローシス細胞と共培養した際、生活がん細胞内にコレステロールが蓄積される可能性が推測された。そこでまず、細胞内コレステロールレベル変化による細胞の機能変化を検索した。コレステロール-MCD複合体の添加により、細胞内コレステロールを上昇させると、細胞形態は多辺形から扇状へと変化し、細胞遊走能が亢進することが示された。

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  • 口腔扁平上皮癌の間質浸潤と側方上皮内進展:その相反的制御と分子基盤

    研究課題/領域番号:21K09841

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    阿部 達也, 山崎 学, 田沼 順一, 丸山 智

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    これまでに, 口腔扁平上皮癌の癌-非癌界面における蛋白質網羅的解析により, 癌界面部組織に特異的に増加した蛋白質である ladinin-1 (LAD1) が癌細胞の平面遊走と垂直遊走に相反的な制御を行っている可能性が見出されていることに加え, 免疫蛍光染色を用いた解析から, LAD1 抑制細胞における細胞形態変化と, vimentin 陽性細胞の有意な増加, E-cadherin の細胞膜上からの有意な減少および細胞質内陽性像の有意な増加を認めたことから, 上皮間葉転換 (EMT) 様表現型の表出に関わっている可能性が考えられていた.
    また, EMT 関連遺伝子の発現変動を LAD1 発現抑制下で検討すると, LAD1 発現を抑制した口腔扁平上皮癌培養細胞株 HSC-2 および HSC-4 で, WNT5A 遺伝子の有意な発現増加が認められたことから, WNT pathway のなかでも, 特に EMT と細胞平面極性への関連が知られる膜貫通タンパクである ROR2 の関連性を検討した. LAD1 の発現抑制下での ROR2 遺伝子発現は, 特に HSC-4 で WNT5A 発現と連動性がみられたことから, LAD1 の発現変動に伴う細胞遊走極性と, EMT 様表現型の発現に, ROR2 の関連性が示唆され, 現在, 同じく siRNA 法での ROR2 発現抑制下での LAD1 および EMT に関連した vimentin・E-cadherin の発現変動, また LAD1・ROR2 の共発現抑制の系を検討中である.

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  • クリニカルシーケンス実現へ向けた舌癌多段階発がんモデルにおける基礎的研究

    研究課題/領域番号:19K10069

    2019年4月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    田沼 順一, 山崎 学, 丸山 智

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    口腔扁平上皮癌(OSCC)の発生は, 正常から上皮性異形成を辿ることが多く, これまでの口腔がん研究は,点(de novo)をターゲットにしたもので, ヒト癌で見られる多段階発がんの解明に不可欠な線(Carcinoma Sequence)を理解する解析方法が無かった.
    そこで本研究は, LBC法を口腔がん発生モデルに応用する事で, 同一検体から免疫細胞染色や遺伝子解析を可能にした. そしてこの結果から, Brd4とc-Mycが経時的及び早期段階(NILMとLSILの間)で発現量が上昇することは,口腔細胞診の判定の精度を向上させるだけでなく,口腔がん早期発見に有用なマーカーになると期待できる.

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  • 唾液腺腫瘍の低酸素応答性増殖機構を標的とした抗腫瘍治療法の創出

    研究課題/領域番号:18K09740

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    丸山 智, 山崎 学, 田沼 順一

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    低酸素誘導因子(HIF)の標的分子であるCD73が細胞機能に果たす役割を検討した。唾液腺多形腺腫由来細胞系SM-APを通常及び低酸素条件下で培養し、HIF-1αおよびCD73の発現、細胞遊走能さらにCD73合成レベルをsiRNA法で制御したときの細胞増殖能について検討した。HIF-1α遺伝子・蛋白質は48時間低酸素培養下で核に高発現し、CD73発現も高発現がみられた。低酸素条件下において細胞遊走能は亢進し、CD73発現を抑制すると細胞増殖は抑制された。以上より、低酸素状態でHIF-1αを活性化させることで、多形腺腫細胞はCD73を高発現させ、細胞の増殖・遊走を促進していることが示唆された。

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  • 口腔扁平上皮癌の非癌上皮細胞との衝突界面におけるアクチン重合配置の分子制御

    研究課題/領域番号:18K09550

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    阿部 達也, 丸山 智, 柿原 嘉人

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    口腔扁平上皮癌(OSCC)の病理組織標本のタンパク質網羅的検索により、ladinin-1 (LAD1)が非癌組織に接する癌組織で高発現することを報告した。しかし, LAD1の癌細胞における役割は不明であることから、その機能を検討することとした。OSCC培養細胞株を用いた発現抑制実験で、LAD1抑制細胞は増殖能低下, 平面的細胞遊走能低下、三次元的細胞遊走能促進を示した。また、LAD1は細胞内でアクチンアークに局在し、LAD1発現抑制下でlamellaの伸展低下、上皮様形態の消失を示した。LAD1がアクチン分子制御を介し細胞遊走を制御するとともに、上皮形態・性質維持に関連する可能性が示唆された。

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  • 細胞死を起点とするがん進展機構:ダイイングコードの解明と標的化戦略

    研究課題/領域番号:18K09533

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    山崎 学, 田沼 順一, 丸山 智

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    口腔扁平上皮癌を含む悪性腫瘍では、細胞死をきたしたがん細胞が高頻度に認められるが、このような死細胞の意義は十分に解明されていない。本研究では、「細胞死をきたしたがん細胞が周囲のがん細胞を活性化させ、がん進展促進に寄与する」という仮説のもと、口腔扁平上皮癌由来培養細胞を用いて仮説を検証した。ネクローシスを誘導したがん細胞との共培養により、生活がん細胞の増殖能、遊走・浸潤能が亢進した。その際、生活がん細胞ではNF-kBシグナリング経路の活性化、種々の炎症性サイトカイン産生が誘導された。以上から、細胞死をきたしたがん細胞が周囲のがん細胞を活性化させることで、がん進展の起点となる可能性が示された。

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  • 歯周炎組織中におけるアルツハイマー病原因分子のネットワーク解析

    研究課題/領域番号:15K11382

    2015年4月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    久保田 健彦, 丸山 智

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    Amyloid beta (A4) precursor protein (APP), Neprilysin (NEP) が歯周炎罹患歯肉局所で有意に発現上昇していること、発現細胞がAPPがMacrophagesであることに対し、NEPでは炎症の程度によりその発現細胞に違いが見られ好中球、線維芽細胞に発現を認めた。(Archs Oral Biol 2017)。歯周炎罹患歯肉組織の炎症性組織代謝についてマトリックス破壊酵素 (MMPs) とインヒビターのバランスからアルツハイマー病関連分子の発現調節に至る一連の研究成果を学術賞受賞を機に総説にまとめた(日本歯周病学会雑誌2018)。

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  • 唾液腺腫瘍の低酸素レベル細胞外環境におけるエネルギー代謝調節機構

    研究課題/領域番号:15K11069

    2015年4月 - 2018年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    丸山 智, 阿部 達也, 山崎 学, 程 クン, 朔 敬

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    唾液腺多形性腺腫の間質は乏血管性の特徴があることから、低酸素環境下でのがん細胞の生存・増殖を可能にしているエネルギー代謝調節機構を明らかにするために、多形性腺腫由来細胞におけるHIF-1に関連したがんの代謝に重要な因子であるMYCの発現レベルおよび細胞機能に果たす役割を検討した。HIF-1α遺伝子・蛋白質は48時間低酸素培養下で高発現し、MYCともに核への局在がみられた。 MYC発現を抑制すると細胞増殖のみだけでなく遊走も抑制された。以上より、多形性腺腫細胞はMYCを高発現することで、低酸素状態での細胞の生存・増殖を維持していることが示唆された。

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  • 同種アポトーシス細胞貪食によって誘導される口腔扁平上皮癌の細胞活性化機序

    研究課題/領域番号:15K11006

    2015年4月 - 2018年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    山崎 学, 阿部 達也, 丸山 智, 程 クン, 朔 敬

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    病理組織標本でがん細胞による同種アポトーシス細胞貪食がしばしば見出されるが、本現象の生物学的意義は不明である。そこで「がん細胞は同種のアポトーシス細胞を貪食することで、自身の細胞機能を活性化する」という仮説を立て、検証した。アポトーシスを誘導した培養細胞を同種生活細胞と共培養すると、多くの生活細胞がアポトーシス細胞を細胞質内に取り込んだ。アポトーシス細胞は貪食細胞のファゴソームに局在しており、貪食はRac1阻害剤により抑制された。さらに、がん細胞の遊走浸潤能はアポトーシス細胞貪食後に亢進した。これより、同種アポトーシス細胞貪食によるがん細胞機能活性化が示され、新規治療標的として期待される。

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  • 口腔扁平上皮癌細胞におけるヘモグロビン誘導性角化機序と角化細胞死への経路

    研究課題/領域番号:15K15693

    2015年4月 - 2017年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的萌芽研究

    提供機関:日本学術振興会

    朔 敬, 程 クン, 丸山 智, 山崎 学, 阿部 達也, 田中 昭男

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    配分額:3510000円 ( 直接経費:2700000円 、 間接経費:810000円 )

    口腔扁平上皮癌における角化は形態学的には皮膚型の正角化で特徴づけられ、分子レベルではケラチン17の発現亢進で規定されることを確定した。異角化特異的ケラチン17の発現は、血管外漏出した赤血球由来のヘモグロビン貪食によって惹起され、ヘモグロビン刺激は口腔扁平上皮癌細胞にケラチン17のみならず、OH-1、PAR-2、14-3-3σ、YAPなどの機能分子の発現を誘導し、細胞死経路への誘導のみならず細胞増殖と細胞遊走・浸潤性にも寄与していた。この異角化分子機序は当初は想定外の口腔扁平苔癬における細胞死誘導に適用され、角化を指標にした細胞診断への応用にまで展開し、挑戦的萌芽研究に相応しい成果となった。

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  • ミャンマーにおける噛みタバコ習慣関連口腔がん発症に関する分子病理疫学的研究

    研究課題/領域番号:26305032

    2014年4月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    朔 敬, 田中 昭男, 山崎 学, 丸山 智, 阿部 達也, 稲井 哲一朗, 程 クン

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    配分額:15990000円 ( 直接経費:12300000円 、 間接経費:3690000円 )

    口腔癌と上皮内癌を含む前癌病変症例をミャンマーの研究協力者の支援により収集し、わが国の症例を加えて、それら病理組織標本についてバーチャルスライドを利用した双方向検討で、上皮内癌の診断根拠となる病理組織所見を抽出し、同所見を口腔癌細胞の生物学的特性の解析実験から説明し、科学的根拠に基づいて病理診断精度を高めることができた。ミャンマーでの調査では、噛みタバコ常習者担癌患者群・非常習者からななる対照群について解析し、黄緑色野菜・果物摂取量の高い対照群で口腔粘膜病変の頻度が低く、血中βカロチン高レベルとの相関も判明した。ミクロ・マクロ双方向アプローチで口腔癌の診断と予防に関する提言を行うことができた。

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  • アジア民族間の口腔表在性癌発症背景の分子病理疫学的比較研究

    研究課題/領域番号:25305035

    2013年4月 - 2017年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    程 クン, 丸山 智, 山崎 学, 阿部 達也, 朔 敬

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    配分額:18200000円 ( 直接経費:14000000円 、 間接経費:4200000円 )

    高齢化社会への移行に伴い口腔がん、とりわけ表在性扁平上皮癌、が増加しているが、その発生背景を究明するため、アジア諸国とわが国の口腔表在性癌症例を比較検討することを計画しして、各地で症例を収集した。まず、科学的根拠に基づく病理診断基準を確立し、その基準にしたがった診断法を各地の研究施設間で均霑化した。ついで、口腔表在性癌の病因は各地で大きく相違するにも関わらず、特定分子の発現を客観的指標に診断を実践することの正当性を証明した。とくに、口腔表在性癌に特徴的に高分化傾向はケラチン(K)17発現で規定される皮膚型正角化という特異的共通項で括られるという事実を確認し、その細胞生物学的意義も説明しえた。

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  • 口腔扁平上皮癌の浸潤開始スイッチ関連分子のプロテオーム解析

    研究課題/領域番号:25462849

    2013年4月 - 2016年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    程 クン, 丸山 智, 山崎 学, 阿部 達也, 朔 敬

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    口腔扁平上皮癌の浸潤性が獲得される機序の詳細は未だ不明である。そこで、非浸潤性の上皮内癌と明瞭な遊離胞巣を伴う浸潤癌の組織標本を用いて病巣周囲に発現している蛋白質を網羅的に解析して、腫瘍実質と周囲正常粘膜、腫瘍実質-間質界面で、癌細胞と非癌細胞または癌細胞と宿主間質細胞のあいだにどのようなクロストークが生じて浸潤性の決定がなされるのかを免疫組織化学法を応用して顕微組織分画した試料をプロテオーム解析した。その結果、浸潤界面形成を特徴づける蛋白質分子群を同定し、浸潤開始の機序を理解する端緒としえた。病理組織学的な浸潤レベルの認知・判定を科学的客観的に評価する方法にも展望が得られた。

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  • 歯周炎罹患歯肉局所におけるアルツハイマー病関連遺伝子の発現亢進を探る

    研究課題/領域番号:24593119

    2012年4月 - 2016年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    久保田 健彦, 丸山 智, 濃野 要, 中曽根 直弘

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    配分額:5330000円 ( 直接経費:4100000円 、 間接経費:1230000円 )

    (第1報) Amyloid beta (A4) precursor protein, interleukin (IL)-1 beta, C1QAが歯周炎罹患歯肉局所で有意に発現上昇していること、発現細胞がMacrophagesであることを報告(Archs Oral Biol 2014)。(第2報) 歯周炎罹患歯肉組織において、炎症関連経路:Toll-like receptor signaling pathway のMD-2, CD14, IL-1beta, IL-8 及びCXCL-9 mRNA が有意に上昇していることを突き止めた (Opn J Stomatol 2014)。

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  • 多形性腺腫細胞の低酸素応答性細胞外基質改変における転移形質獲得機構

    研究課題/領域番号:24592829

    2012年4月 - 2015年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    丸山 智, 阿部 達也, 山崎 学, 程 珺, 朔 敬

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    配分額:5330000円 ( 直接経費:4100000円 、 間接経費:1230000円 )

    唾液腺多形性腺腫の間質表現は多彩かつ乏血管性であることから、低酸素環境下で細胞外基質(ECM)合成を亢進させて多彩な間質表現を実現し、生存・増殖を維持しているという仮説をたて、低酸素下でのECM合成能および細胞機能を検討した。HIF-1α遺伝子・蛋白質は48時間低酸素培養下で高発現・核移行し、腫瘍間質に豊富なECM分子のperlecan、fibronectinの合成が促進された。さらにsiRNA法でECM発現を抑制すると、細胞増殖が抑制された。以上より、多形性腺腫には低酸素刺激によってECM合成を亢進させることで、低酸素状態にも関わらず細胞増殖を維持する機構がそなわっていることが示唆された。

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  • アジア・アフリカの噛みタバコ習慣関連口腔がん発症に関する分子病理疫学的研究

    研究課題/領域番号:23406038

    2011年4月 - 2015年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    朔 敬, 程 珺, 丸山 智, 山崎 学, 阿部 達也

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    配分額:14820000円 ( 直接経費:11400000円 、 間接経費:3420000円 )

    口腔扁平上皮癌の病因として関連づけられてきた噛みタバコ習慣の広がる地域の口腔癌症例を収集して病理疫学的に解析した。疫学的に噛みタバコ習慣者の非習慣者を対比したコホート調査をミャンマーで開始した。その結果、同習慣による口腔粘膜変化との関連、すなわち、口腔粘膜下線維症と異型上皮、上皮内癌等の前癌病変の随伴が確認された。そこで、それら前癌病変の病理組織学的特性について解析したところ、上皮内血管や正角化型異型上皮等の特徴的病態をみいだし、それらの生物学的意義について実験的に解析した。以上を総合して前癌病変の診断基準を見直し、われわれの基準が外科手術の予後等にも反映する客観性があることも判明した。

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  • Dual Energy CTイメージングによる顎骨骨髄微小循環描出の試み

    研究課題/領域番号:23592760

    2011年 - 2013年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    田中 礼, 林 孝文, 依田 浩子, 池 真樹子, 大島 勇人, 丸山 智

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    Dual Energy CT Imaging(DEI)を用いて下顎骨骨髄の微小血管分布を画像化することを目的に、病変切除のため下顎骨区域切除術が施行された患者の顎骨病理標本、および当該部位のCT画像を対象とし、組織切片上で骨髄の一定範囲内の微小血管分布を主観的に評価した。下顎骨切除術前のCT画像データからMPR画像を構築し組織像と照合した。評価対象の骨髄部は非常に小さく、かつ脂肪細胞の占める割合が圧倒的に大きく、至適CT画像生成方法の確立には至らなかった。組織切片上の微小血管の分布から、下顎骨骨髄の微小血管の割合は、CT画像に何らかの濃度変化を引き起こすほどには大きくないと思われた。

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  • 石灰化嚢胞性歯原性腫瘍由来CCOT細胞系における幻影細胞化と石灰化の分子機構

    研究課題/領域番号:22592033

    2010年 - 2012年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    程 〓, 丸山 智, 山崎 学, 朔 敬, 阿部 達也

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    歯原性腫瘍に特徴的な幻影細胞が最も顕著な石灰化嚢胞性歯原性腫瘍(calcifying cystic odontogenic tumor, CCOT)の性格は十分に理解されていない。われわれは同腫瘍由来の細胞株樹立に成功したので、これを用いて幻影細胞成立、二次的悪性化機序を試験管内で検討した。その結果、幻影細胞の特徴的細胞像はパールカンなどの細胞外基質分子が細胞外に分泌されずに沈着することが原因であることをつきとめた。幻影細胞の特徴的な細胞質、脱核の機構など長年の懸案が説明でき、CCOT 由来細胞の腫瘍性格を明確にすることで、CCOTの診断から治療までの臨床的対応に科学的根拠をもってあたることができるようになった。

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  • 唾液腺多形性腺腫における低酸素応答性増殖機構: SM-AP細胞系による解析

    研究課題/領域番号:22791810

    2010年 - 2011年

    制度名:科学研究費助成事業

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    丸山 智

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    唾液腺多形性腺腫の間質表現は多彩であるが、乏血管性であることも特徴である。したがって間質をふくめて多形性腺腫組織は低酸素状態であるという仮説をたて、これを証明するために多形性腺腫由来細胞の増殖における低酸素依存性を試験管内で検討した。その結果、多形性腺腫由来細胞では、低酸素下でのHIF-1α蛋白質の高発現およびVHL遺伝子・蛋白質の低発現によりHIF-1αの分解抑制機構がはたらいており、低酸素状態で核移行したHIF-1αによりVEGFの高発現レベルを維持されることが示された。試験管内でえられた以上の結果は、ヌードマウス移植腫瘍組織・ヒト多形性腺腫組織手術材料の生体組織でも追認され、ヌードマウス背部皮下移植腫瘍内酸素分圧は周囲皮下組織に比して有意に低いことも確認された。以上の機序によって、低酸素環境で増殖さらには転移形質が誘導されている可能性が示唆された。

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  • 薬剤性歯肉線維化局所におけるコラゲナーゼインヒビターの役割

    研究課題/領域番号:21592622

    2009年 - 2011年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    久保田 健彦, 中曽根 直弘, 丸山 智, 濃野 要

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    第1報「TIMP-3, TIMP-4の歯肉増殖症、歯周炎罹患歯肉組織中における遺伝子発現レベルおよび免疫組織化学的局在」を当該分野で初めてArchs Oral Biology(2009)に報告した。本研究シリーズの成果について2009年度日本歯科保存学会学会学術賞を授与された(Review 2010)。第2報「薬剤性歯肉増殖症に特異的な遺伝子発現」をマイクロアレイとデータマイニング遺伝子発現解析及び第3報:「歯肉増殖症と歯周炎の特異的遺伝子発現パターン」に関しそれぞれArchs Oral Biology(2011), J Periodont Res(2011)に報告した。

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  • 東アジア地域における口腔粘膜表在性癌に関する比較分子病理疫学的研究

    研究課題/領域番号:20406029

    2008年 - 2011年

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    程 ?, 丸山 智, 朔 敬, 依田 浩子, 山崎 山崎

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    配分額:16770000円 ( 直接経費:12900000円 、 間接経費:3870000円 )

    わが国をはじめ高齢化社会への移行にともなって口腔癌が増加しているが、その一因は口腔粘膜内多発・再発性の表在性癌の増加による。その発生背景を明らかにするため、東アジア諸国とわが国の表在性癌症例を比較検討した結果、地域差・病因の相違に関わらず、表在性癌が上皮内癌を中心として異型上皮から微小浸潤癌までを包括する病変複合体であることを明確にし、その認識のためには上皮内癌の病理診断を科学的・客観的に実践する必要があるので、その手立てを確立した。

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  • 唾液腺多形性腺腫の低酸素環境における増殖機構

    研究課題/領域番号:20791331

    2008年 - 2009年

    制度名:科学研究費助成事業

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    丸山 智

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    唾液腺多形性腺腫の間質表現は多彩であるが、乏血管性であることも特徴である。したがって間質をふくめて多形性腺腫組織は低酸素状態であるという仮説をたて、これを証明するために多形性腺腫由来細胞の増殖における低酸素依存性を試験管内で検討した。その結果、ヒト唾液腺多形性腺腫由来細胞系SM-APにおけるHIF-1αの遺伝子発現レベルは低酸素培養で変動しなかったが、VEGF遺伝子は増強された。一方、蛋白質レベルでは、低酸素下でHIF-1αおよびVEGFが上昇し、vHLは低下し、HIF-1αは核移行していた。以上の結果から、低酸素環境下のSM-AP細胞では、HIF-1αがvHLで分解されずに核移行しているためにVEGF発現が強調されていることが判明した。すなわち、多形性腺腫では、乏血管性環境にもかかわらず、というより、むしろ低酸素環境を利用したVEGF依存性の独自な増殖機構を獲得していることが示唆された。

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  • アジアから東アフリカまで広がる噛みタバコ習慣による口腔がん発症機構

    研究課題/領域番号:19406030

    2007年 - 2010年

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    朔 敬, 程 〓, 丸山 智, 依田 浩子, 山崎 学

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    配分額:16640000円 ( 直接経費:12800000円 、 間接経費:3840000円 )

    口腔がんの発生要因として特定されてきたアジア・アラビア・東アフリカに普遍的な噛みタバコ習慣による発癌と、発生要因の特定しえないわが国の口腔がんの発癌とを疫学的調査と分子病理学的解析で比較検討した。その結果、口腔粘膜下線維症が被覆上皮の悪性転化の背景となる組織構築を検討し、表在性癌の組織学的特異性、そのなかでも異型上皮と上皮内癌,微小浸潤癌の病理診断基準を実用的レベルでほぼ確立することができた。

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  • 口腔粘膜・皮膚の付属器におけるパールカンの役割-上皮過剰発現系マウスによる解析-

    研究課題/領域番号:19592105

    2007年 - 2008年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    依田 浩子, 丸山 智, 程 〓, 朔 敬

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    上皮組織構築とくに口腔粘膜、皮膚付属器における基底膜型へパラン硫酸プロテオグリカン・パールカンの役割を解明する目的で、パールカン上皮細胞過剰発現系トランスジェニック(Tg)マウスにおけるin vivoでの上皮組織の病的変化について、口腔粘膜および毛包をはじめとする皮膚付属器に着目して組織学的に検索した。その結果、毛包発育過程に乱れが生じ、上皮細胞の分化および毛包発育に関与する増殖因子ならびに転写因子に発現レベルの変化がみられた。したがって、パールカンの持続的発現により上皮細胞分化および皮膚付属器、とくに毛包発育にかかわるシグナル伝達経路が障害され、分化の乱れを生じる可能性が示唆された。
    さらに、パールカンTgマウスにおける口腔粘膜・皮膚創傷治癒実験では、表皮再生が促進されており、パールカンがケラチノサイトの増殖および分化を制御している可能性がしめされた。したがって、上皮細胞の産生するパールカンが上皮組織構築に重要な役割を果たしていることが明らかとなった。

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  • 口腔癌細胞浸潤にともなう間質誘導スイッチング機構の分子病理学的解析

    研究課題/領域番号:18390486

    2006年 - 2008年

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    朔 敬, 程 〓, 丸山 智, 鈴木 誠, 依田 浩子

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    配分額:18450000円 ( 直接経費:15300000円 、 間接経費:3150000円 )

    扁平上皮癌の腫瘍性間質誘導が、浸潤を契機に実質細胞から間質細胞に移管される(スイッチング)のではないかという仮説をたて、これを証明するために扁平上皮癌細胞と線維芽細胞の共培養系を作製して、細胞外基質分子代謝を軸に検討し、口腔癌組織の結果と照合した.その結果、上皮内癌に相当する分離共培養では癌細胞側に、浸潤癌に相当する混合共培養では、線維芽細胞側にECM 産生の主体があり、間質誘導が扁平上皮癌浸潤によって開始することを証明し、この概念を病理診断の理論的背景として適用することに成功した.この結果、非浸潤性腫瘍の腫瘍細胞間隙の細胞外基質を腫瘍細胞によって産生される上皮内基質という概念でとらえることを提唱することになった.

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  • 歯原性角化嚢胞モデルとしてのMsx2ノックアウトマウスの顎骨嚢胞

    研究課題/領域番号:18659554

    2006年 - 2007年

    制度名:科学研究費助成事業

    研究種目:萌芽研究

    提供機関:日本学術振興会

    里方 一郎, 鈴木 誠, 朔 敬, 程 ゆん, 丸山 智, 里方 一郎, 伊東 達雄

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    配分額:3300000円 ( 直接経費:3300000円 )

    1.ヒト歯原性角化嚢胞患者におけるのMSX2遺伝子異常解析
    ヒトの歯原性角化嚢胞患者からDNAを抽出し、PCRによってMSX2遺伝子のexonlおよびexon2を増幅し、直接シークエンス法によってそれらの塩基配列を決定し、変異状況を検索した。30例の非症候群性歯原性角化嚢胞患者では、MSX2遺伝子の変異は認められなかった。症候群性歯原性角化嚢胞(母斑基底細胞癌症候群)9家系について解析を行ったところ、1家系にintronlのsplice donor siteの点変異が発見された。この変異によりMSX2 haploinsufficiencyが生じることがin vitroの実験により示された。さらに、症候群性歯原性角化嚢胞の原因遺伝子とされるPTCH1の変異は検出されなかったことより、この家系ではMSX2が症候群性歯原性角化嚢胞の原因遺伝子であると結論した。
    2.Msx2ノックアウトマウスにおけるBMP4の部位特異的強制発現によるレスキュー実験
    Msx2ノックアウトマウスのエナメル上皮細胞におけるBMP4の部位特異的強制発現を行い、BMP4の発現低下を補った場合に歯原性角化嚢胞の形成を阻止できるか調べた。Msx2遺伝子の発現部位に特異的にBMP4を発現するトランスジェニックマウスとMsx2ノックアウトマウスの交配により、エナメル上皮由来細胞に特異的にBMP4を発現するMsx2ノックアウトマウスの作成を行った。歯原性角化嚢胞の発生頻度は、Tg/+;Msx2-/-マウスでは歯原性角化嚢胞の発生頻度がMsx2-/-マウスと比較して差はなかったが、Tg/Tg;Msx2-/-マウスでは、歯原性角化嚢胞の発生頻度がMsx2-/-マウスと比較して有意に低下した。この結果は、BMP4遺伝子の発現低下が歯原性角化嚢胞の形成に重要な役割を果たしていることが考えられた。

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  • 良性歯原性腫瘍の二次的悪性転化機構に関する分子病理学的検討

    研究課題/領域番号:18591999

    2006年 - 2007年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    程 クン, 丸山 智, 朔 敬

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    配分額:3830000円 ( 直接経費:3500000円 、 間接経費:330000円 )

    本研究実施によって、ヒト上顎骨原発石灰化歯原性嚢胞(COT)の外科手術材料より腫瘍細胞単離し、COT1-COT6の6株細胞を樹立した。同細胞系の維持によって、周密化までの培養期間中に経時的に固定または回収して、免疫細胞化学とRT-PCR法による発現分子をおこない、さらに染色体標本のトリプシンG-バンド法による解析によって第9-13染色体の相互転座はじめ種々の染色体レベルの異常をみいだした。これらの細胞はケラチン16やアメロジェニン等の歯原性上皮性格を発現していた。
    細胞系樹立実験と平行して、本学病院の病理診断ファイルから、COTと診断された症例を収集し、再度検鏡後、嚢胞性部分、充実性増殖した部分、浸潤性部分、とくにそれら病変の移行部分を注目して詳細に再検討し、歯原性上皮細胞マーカ、各種細胞外基質とその関連分解酵素、石灰化関連分子等の発現を検索した。その結果、幻影細胞には、パールカン、テネイシン、ファイブロネクチンほかの細胞外基質分子が蓄積しており、これに対応して、MMP7やβカテニンも共発現していることが判明した。すなわち、COTに特徴的な幻影細胞の特徴的形態は細胞外基質の分泌障害によること、さらに、Wntのシグナル伝達経路の変調も生じていたので、それらの分子経路の相互関連が推測された。
    以上の組織ならびに細胞レベルでの検討から、染色体転座および細胞外基質分子分泌異常が複雑かつ相乗的に関与して、良性歯原性腫瘍COTの悪性転化が成立している可能性が示唆されたわけで、良性腫瘍の二次的悪性転化機構の具体的な分子背景を新たに追加することができた。

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  • 唾液腺多形性腺腫の乏血性環境における増殖機構

    研究課題/領域番号:18791345

    2006年 - 2007年

    制度名:科学研究費助成事業

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    丸山 智

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    配分額:3500000円 ( 直接経費:3500000円 )

    (1)免疫細胞化学的検索
    ヒト唾液腺多形性腺腫より樹立したSMAP1/4細胞株を用いて、1.2x10^4細胞をチャンバースライドに植え込み、経時的に4%パラフォルムアルデヒドで固定後、低酸素応答性の転写因子であるHIF-1aおよびHIF-1aにより増幅されるといわれている血管内皮増殖因子であるVEGF、かつHIF-1aとJab-1を介して関連があることがすでにわかっているがん抑制遺伝子であるp53に対する各抗体をもちいて、これらの発現を蛍光抗体法にて検討した。その結果、低酸素下で、HIF-1aおよびVEGFの発現レベルが高い傾向がみられた。さらにHIF-1aについては、しばしは核に移行している像がしばしばみとめられ、degradationを受けずに核に移行したHIF-1aにより、VEGFの発現が促進された可能性が示唆された。また変異のみられたp53の発現はみとめられなかった。
    (2)実験結果の評価と研究の総括
    以上の実験結果より、多形性腺腫由来細胞では、pVHLの低発現およびp53の変異によりHIF-1aのdegradationの抑制機構がはたらいており、低酸素状態で核に移行したHIF-1aによりVEGFの高い発現レベルを維持することで、低酸素環境で増殖さらには転移形質を誘導しているのではないかと考えられた。今後はより詳細にHIF-1a蛋白質の低酸素培養条件下での分解挿制機構を明らかにしていく予定である。

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  • 口腔粘膜上皮<胚細胞>の同定とその二方向性分化経路概念の確立

    研究課題/領域番号:17659576

    2005年 - 2006年

    制度名:科学研究費助成事業

    研究種目:萌芽研究

    提供機関:日本学術振興会

    朔 敬, 程 〓, 丸山 智

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    配分額:3300000円 ( 直接経費:3300000円 )

    マウス口腔粘膜扁平上皮増殖中心細胞の同定とその発現遺伝子の特定:4週齢ICR系マウス腹腔にBrdUを投与して、パラフィン切片を作製し、BrdU取り込み細胞を同定した。その結果、マウス口腔粘膜では、BrdU陽性細胞は上皮基底層第一・二層に分布し、ヒト粘膜とは必ずしも対応しない分布であることが判明した。
    (1)マウス口腔粘膜上皮胚細胞の試験管内分化誘導:前項までに確立したマウス口腔粘膜より扁平上皮胚細胞集団を分離し、試験管内にそれらの胚細胞を単層培養して、分化誘導実験の条件検討を試みたが、細胞維持が困難なために実験系のデザインを検討中である。
    (2)ヒト口腔粘膜異型上皮と上皮内癌における基底細胞分化抗原の免疫組織学的確認:前年度までに確定された増殖細胞抗原として有用なマーカKi-67のほかに、ケラチン分子種のうち、CK13,17,10,16,19、さらに角質分化関連分子のうち、インヴォルクリン、フィラグリン、機能は不明ながらポドプラニンの有用性をヒト口腔粘膜境界病変で免疫組織学的に確認した。とくにCK13消失とCK17出現の対応はもっとも重要な所見と評価された。
    (3)総括:以上より、扁平上皮杯細胞の所在は基底部であることは想定されるが、第一層であるのか第二層であるのかを特定することはなお困難である。しかし、異型細胞が生じて上皮内癌に向かう過程では、基底第二層に増殖中心があることは判明し、角化あるいは基底細胞分化経路に未だ入らない細胞群の存在は確認できた。したがって、少なくともがん幹細胞は上皮基底第二層に存在するという概念を固めることができた。

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  • 上皮組織における基底膜型ヘパラン硫酸プロテオグリカン・パールカンの役割

    研究課題/領域番号:17591902

    2005年 - 2006年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    依田 浩子, 丸山 智, 佐藤 俊哉, 程 くん, 朔 敬, 鈴木 誠

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    配分額:3600000円 ( 直接経費:3600000円 )

    上皮組織とくに歯胚および口腔粘膜の上皮構築における基底膜型ヘパラン硫酸プロテオグリカン・パールカンの役割を解明する目的で、パールカン上皮細胞過剰発現系トランスジェニックマウスを作製し、歯胚組織および口腔粘膜における病的変化について、組織学的および分子生物学的に検索した。さらに歯胚エナメル器を分離後、星状網様細胞の初代培養をおこない、パールカン過剰発現の有無による細胞形態の変化について解析をおこなった。その結果、歯胚組織においては、胎生期Tgマウス臼歯でエナメル器星状網の細胞間隙が著明に拡大し、エナメル器形態の変化とともにエナメル器内の細胞分化にも乱れが生じていた。生後臼歯では、歯冠形態が鈍縁化し、同時に歯根離開も観察された。さらに、Tgマウス歯胚組織の遺伝子発現の解析結果より、出生前後で線維芽細胞増殖因子をはじめとする各種成長因子やMsx-2などの転写因子の遺伝子発現上昇が確認された。したがって、パールカンはエナメル器内の成長因子や転写因子の発現調節に関わり、歯胚エナメル器細胞の分化と、歯冠および歯根形態の誘導を制御していることが示された。さらに、口腔粘膜上皮では、基底細胞の配列の乱れおよび多層化が観察され、上皮過形成ないしは異形成等の口腔粘膜疾患の発症過程において、上皮細胞間へのパールカン過剰沈着が関与している可能性が示唆された。
    以上、本研究結果より、上皮細胞が産生する細胞外基質としてのパールカンが、歯胚組織および口腔粘膜上皮の形態形成を調節していることがあきらかとなり、他の上皮組織(皮膚、皮膚付属器、唾液腺等)の恒常性維持にも重要な役割を果たしていることが推察された。したがって、上皮内基質が上皮組織の構築を制御しているという新たな観点から、今後の上皮再生医療の発展に貢献が期待される研究展望がえられた。

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  • 唾液腺リンパ上皮性癌に特異的にEBウィルス感染の分子病理学的解析

    研究課題/領域番号:16406033

    2004年 - 2006年

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    程 クン, 丸山 智, 朔 敬, 依田 浩子, 大城 和文

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    配分額:11300000円 ( 直接経費:11300000円 )

    本研究実施によって、唾液腺リンパ上皮性癌(LEC)におけるEBVはLMP-1遺伝子を軸に初めて明らかにし得た。唾液腺LEC由来EBVには少なくとも二系統の地埋的変異が存在し、同遺伝子プロモータを含む多様な変異が腫瘍厳正に関与する可能性が示唆された。唾液腺LEC由来の単離遺伝子を再構成して試験管内でその他の由来LMP1遺伝子と比較したところ、顕著な差異がみいだされなかったものの、明らかにNFκB転写因子活性増加作用が確認されたので、同遺伝子の腫瘍細胞活性化に関与していることが証明された。しかし、同時に細胞増殖抑制も出現することが判明したので、この点はさらに検討中である。
    中国各地の施設と手術材料からのLEC細胞の単離をこころみてきた。細胞の維持は困難であったが、選択的リンパ球除去法とコラゲナーゼ細胞分散法とをとりいれることで、他種細胞の混入なしにLEC細胞を調整する方法を検討したところ、現在までに細胞単離後初期培養には成功して、LMP1およびLMP2A等のEBV遺伝子の発現と唾液腺導管上皮ならびに筋上皮細胞性格を確認できたが、株化までには至っていない。
    さらに、LECの背景病変としての可能性を検討するために、類似良性病変のリンパ上皮性嚢胞と良性リンパ上皮性病変症例をさらに収集して病埋組織学的ならびに免疫組織化学的、ウィルス学的な検討をおこなった。しかし、いずれの病変にもEBVの積極的な関与はなかった。したがって、LECの基礎疾患として、唾液腺炎を経過して発がんする経路は否定された。

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  • 良性口腔腫瘍の二次的悪性転化機構に関する分子病理学的検討

    研究課題/領域番号:16591821

    2004年 - 2005年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    程 くん, 丸山 智, 朔 敬, 依田 浩子, 大城 和文

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    配分額:3600000円 ( 直接経費:3600000円 )

    本研究では、唾液腺に発生する良性腫瘍・多形性腺腫の二次的悪性転化を中心に検討し、良性腫瘍から悪性腫瘍が発生する機序について考察した。多形性腺腫内には異型細胞が出現する頻度が高く、巣状癌が二次的に悪性化する可能性を提言してきたからである。
    まず、ヒト耳下腺多形性腺腫組織から不死化細胞を単離し、6株の細胞系SMAPを樹立し、これら細胞について種々の検討をおこなった。SMAP1-3は導管上皮、SMAP4-6は筋上皮への分化性格が有していた。これらの細胞は平均107本の染色体、核型5nの異数倍性、さらに第13番染色体q12と第9番染色体p13の相互転座が共通してみいだされ、同部より遠位の遺伝子座欠失で同位のp16遺伝子など癌化関連遺伝子の機能喪失が示唆された。またp53遺伝子異常も発見された。したがって、以上のような遺伝子レベルでの異常をもとに悪性形質が獲得されていくことが示唆された。
    また、多形性腺腫における被膜浸潤と脈管侵襲の発生頻度を検討したところ、被膜浸潤は検討症例ほぼ全例ときわめて高頻度で、被膜外進展も約20%の症例でみられた。さらに静脈侵襲事例は約15%であった。侵襲部位の組織学的特徴は粘液様間質で乏血管性の特徴があった。その乏血管分布性の背景にはVEGFと特徴的スプライシング様式とHIF-1α高発現の関連があった。したがって、多形性腺腫の悪性形質獲得には、これらの生物学的態度も重要な貢献をしている可能性が示唆された。
    ついで、ヒト顎骨に発生した黒色プロゴノーマ由来細胞株も作製し、その染色体に、SMAP細胞同様、第9-第13染色体の相互転座がみられ、良性腫瘍の悪性転化の解析に重要な変化とみなされ、今後の検討方向が示された。

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  • アジアに広がる〈噛みたばこ習慣〉による口腔がん発症機構の分子病理学的解析

    研究課題/領域番号:15256005

    2003年 - 2006年

    制度名:科学研究費助成事業

    研究種目:基盤研究(A)

    提供機関:日本学術振興会

    朔 敬, 程 クン, 丸山 智, 依田 浩子, 宮崎 秀夫, 長尾 徹, 浅川 義範, 鈴木 誠, 大城 和文

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    配分額:34060000円 ( 直接経費:26200000円 、 間接経費:7860000円 )

    (1)症例収集ならびに疫学調査:噛みたばこ習慣の有無のほか口腔癌患者の臨床的事項および腫瘍病理組織型や粘膜下線維症を検討した。台湾、インド、バングラデッシュ、スリランカ、イエメン、マダガスカル、ミャンマーを踏査し、習慣と口腔癌発生頻度の関連を検討した。
    (2)口腔粘膜前がん病変の診断と上皮内基質:免疫組織化学的解析結果を応用して新たに口腔粘膜前がん病変の病理組織学的概念を発展させた。すなわち、二層性異型上皮の認識が腫瘍性異型上皮の診断に有用であること、上皮内に沈着するパールカンほかの細胞外基質を証明して上皮内基質という概念を提案し、それが前がん病変診断に有用であることを明らかにした。
    (3)口腔粘膜下線維症の解析:噛みたばこ地域から収集した粘膜下線維症(OSF)症例によって、その進行度分類を提案し、それが細胞外基質の沈清様式と関連があることをしめした。線維症の進展に脈管分布が関連し、局所の低酸素状態が口腔発がん背景となる基礎データをえた。
    (4)扁平上皮癌のがん関連遺伝子:収集した口腔粘膜扁平上皮癌、上皮内癌、異型上皮症例について、組織化学、微小切り出し、RT-PCRによる解析をすすめた結果、噛みたばこ背景の有無にかかわらず共通するp53遺伝し変異様式を明らかにした。
    (5)噛みたばこ成分の解析:噛みたばこ材料について有機化学的に精密分析をおこない、その成分は地域をこえて基本的には同様の構成であることが判明した。
    (6)総括:以上のとおり、噛みたばこ習慣による口腔癌の多面的な検討により、わが国の口腔癌との類似点を明らかにできたので、わが国の口腔癌発症機構を検討していくために重要な示唆がえられるとともに、病理組織診断精度を格段に向上させることができた。

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