Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.3892/or.2018.6665

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.humpath.2016.07.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.pathol.2016.02.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1111/jop.12197

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1038/labinvest.2014.108

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background/Objectives: Cancer organoids have emerged as a valuable tool of three-dimensional (3D) cell cultures to investigate tumor heterogeneity and predict tumor behavior and treatment response. We developed a 3D organotypic culture model of oral squamous cell carcinoma (OSCC) to recapitulate the tumor–stromal interface by co-culturing four cell types, including patient-derived cancer-associated fibroblasts (PD-CAFs). Methods: A stainless-steel ring was used twice to create the horizontal positioning of the cancer stroma (adjoining normal oral mucosa connective tissue) and the OSCC layer (surrounding normal oral mucosa epithelial layer). Combined with a structured bi-layered model of the epithelial component and the underlying stroma, this protocol enabled us to construct four distinct portions mimicking the oral cancer tissue arising in the oral mucosa. Results: In this model, α-smooth muscle actin-positive PD-CAFs were localized in close proximity to the OSCC layer, suggesting a crosstalk between them. Furthermore, a linear laminin-γ2 expression was lacking at the interface between the OSCC layer and the underlying stromal layer, indicating the loss of the basement membrane-like structure. Conclusions: Since the specific 3D architecture and polarity mimicking oral cancer in vivo provides a more accurate milieu of the tumor microenvironment (TME), it could be crucial in elucidating oral cancer TME.

DOI： 10.3390/biomedicines12102373

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-024-74041-z

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The fatty acid receptor CD36 is expressed on various malignant cells and is suggested to contribute to tumor progression. CD36 is also expressed by several immune cells and involved in immune responses and may be a potential target in cancer immunotherapy. In this study, we investigated whether the selective inhibition of CD36 can inhibit tumor progression and facilitate an antitumor immune response in oral squamous carcinoma cells (OSCCs). We assessed the effects of sulfosuccinimidyl oleate sodium (SSO), a CD36 inhibitor, on the proliferation apoptosis and alteration in tumor cell surface expression levels of immune accessory molecules in vitro. We also assessed whether SSO-treated OSCCs could promote a T cell response via a Mixed Lymphocyte Reaction (MLR) assay. We also investigated the direct antitumor effects and immunomodulatory effects of SSO using a mouse oral cancer OSCC model. SSO treatment significantly inhibited OSCC proliferation, increased apoptotic cell death, and upregulated the cell surface expression of several immune accessory molecules, including CD83, MHC-Class II, and PD-L1. SSO-treated OSCCs augmented T cell proliferation following MLR. In vivo SSO administration significantly attenuated mouse tumor growth with an increased proportion of immune cells, including CD4+ T, CD8+ T, and dendritic cells; it also decreased the proportion of immune suppressive cells, such as myeloid-derived suppressor and regulatory T cells. These results suggest that the selective inhibition of CD36 can induce direct and indirect antitumor effects by facilitating host antitumor immune responses in OSCCs.

DOI： 10.3390/ijms25179438

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11626-024-00958-4

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Other Link： https://link.springer.com/article/10.1007/s11626-024-00958-4/fulltext.html

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Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumours, warranting novel treatments. Here, we examined the therapeutic efficacy of inhibiting p21 activated kinase 4 (PAK4) in OSCC and determined its immunomodulatory effect by focusing on the enhancement of anti-tumour effects. We examined PAK4 expression in OSCC cells and human clinical samples and analysed the proliferation and apoptosis of OSCC cells following PAK4 inhibition in vitro. We also investigated the effects of in vivo administration of a PAK4 inhibitor on immune cell distribution and T-cell immune responses in OSCC tumour-bearing mice. PAK4 was detected in all OSCC cells and OSCC tissue samples. PAK4 inhibitor reduced the proliferation of OSCC cells and induced apoptosis. PAK4 inhibitor significantly attenuated tumour growth in mouse and was associated with increased proportions of IFN-γ-producing CD8+ T-cells. Furthermore, PAK4 inhibitor increased the number of dendritic cells (DCs) and up-regulated the surface expression of various lymphocyte co-stimulatory molecules, including MHC-class I molecules, CD80, CD83, CD86, and CD40. These DCs augmented CD8+ T-cell activation upon co-culture. Our results suggest that PAK4 inhibition in OSCC can have direct anti-tumour and immunomodulatory effects, which might benefit the treatment of this malignancy.

DOI： 10.1038/s41598-024-64126-0

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Publishing type：Research paper (scientific journal)   Publisher：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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Publishing type：Research paper (scientific journal)   Publisher：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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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajoms.2023.11.007

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Language：English   Publisher：(一社)日本癌学会  

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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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Publishing type：Research paper (scientific journal)   Publisher：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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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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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajoms.2022.02.007

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/osi2.1155

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/osi2.1155

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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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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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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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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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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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OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

DOI： 10.1007/s11282-021-00533-7

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OBJECTIVE: Accumulating evidence has demonstrated the protumor role of estrogen receptor (ER)-mediated signaling in multiple cancer types, which is distinct from this signaling in sex steroid-dependent organs. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. STUDY DESIGN: We assessed the expression of ERα and ERβ in human OSCC tissues by immunohistochemistry and evaluated the expression of both receptors in OSCC cell lines by immunoblotting and flow cytometry. To further assess the contribution of ER-mediated signals to oral cancer progression, proliferation, invasion, and chemosensitivity, cell lines were stimulated with the ER agonist β-estradiol. RESULTS: Immunohistochemical analysis of OSCC tissues showed that ERβ was present in the cytoplasm and nuclei of OSCC cells. In contrast, ERα was not detected in any of the cases analyzed. Additionally, the proliferation and invasiveness of OSCC cells were significantly elevated following stimulation with β-estradiol. Chemotherapeutic agent-induced apoptosis of cancer cells was attenuated by pretreatment with β-estradiol. CONCLUSIONS: ER-mediated signaling plays a crucial role in oral cancer progression by facilitating the proliferation, invasion, and chemoresistance of OSCC cells, indicating its potential for developing novel targeted therapies for this type of cancer.

DOI： 10.1016/j.oooo.2021.04.006

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R2TP is a well-conserved molecular chaperone complex, composed of Pontin, Reptin, RPAP3, and PIH1D, in eukaryotes. Recent studies have suggested an involvement of R2TP in cancer development. However, it remains unclear if it is related to the development of oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer. Here, we identify and investigate the function of R2TP in OSCC development. Immunohistochemical analysis reveals that all of the R2TP components are strongly expressed in normal oral epithelia and OSCC tissues, where actively proliferating cells are abundant. Co-immunoprecipitation assay identifies that R2TP components form a protein complex in OSCC-derived HSC4-cells. Knockdown experiments show that all R2TP components, except for RPAP3, are required for the cell proliferation and migration of HSC-4 cells. Furthermore, we reveal that Pontin contributes to a gain-of-function (GOF) activity of mutp53-R248Q in HSC-4 cells by regulating phosphorylation levels of mutp53 at Ser15 and Ser46. To our knowledge, this study is the first to report the functional involvement of R2TP and its components in the malignant characteristics of OSCC cells.

DOI： 10.1016/j.bbrc.2021.02.074

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Anti-laminin 332 mucous membrane pemphigoid (MMP) is characterized by circulating anti-laminin 332 autoantibodies, with a high risk of concurrent malignant neoplasms. We report a case of anti-laminin 332 MMP manifesting as a desquamative gingivitis. A 45-year-old woman experienced painful erythema and occasional bullous lesions on the gingiva despite good oral hygiene and plaque control. Intraoral examination revealed gingival inflammation with desquamation. Biopsy showed subepithelial cleft formation suggesting a subepidermal blister. Direct immunofluorescence revealed the deposition of IgG and IgA in the epithelium. Accordingly, we diagnosed anti-laminin 332 MMP and treated with systemic corticosteroids. The oral lesion resolved after 3 months.

DOI： 10.1002/osi2.1073

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Churchill Livingstone  

The authors regret that although we stated “four cases with lesions involving the floor of the mouth and two with lesions involving the hard palate have been reported”, none actually involved the oral floor. We erroneously called the base of the tongue as the floor of the mouth. Therefore, we would like to correct this to “four cases with lesions involving the base of the tongue and two with lesions involving the hard palate have been reported”. The authors would like to apologise for any inconvenience caused.

DOI： 10.1016/j.ijom.2021.05.021

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Language：Japanese   Publisher：(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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Other Link： 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

Language：Japanese   Publisher：新潟歯学会  

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

52歳女。舌の違和感を主訴に近医を受診し、右側舌腫瘍を指摘された。他院のMRIで腫瘍性病変を認められ、当科での加療を勧められて来院した。右側舌下面粘膜下に15×15×15mm大の比較的境界明瞭な弾性硬の腫瘤を認めた。画像所見からは腺系腫瘍が示唆され、良悪性を含めた病理組織学的診断目的に生検を行ったが、組織型の確定には至らず、舌癌の診断のもと全身麻酔下に舌部分切除術を施行した。切除標本の病理組織所見は、淡明細胞の胞巣状増殖が主体ながら、粘液産生を示す二相性腺管がわずかに混在していたことから、鑑別疾患として筋上皮癌、上皮筋上皮癌、多型腺癌、明細胞癌が挙げられた。免疫染色によって筋上皮癌、上皮筋上皮癌、多型腺癌は否定され、EWSR1遺伝子のFISH解析によって明細胞癌も否定されたため腺癌NOS(not otherwise specified)と診断した。術後4年の現在まで再発・転移は認めていない。

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01073&link_issn=&doc_id=20201130470003&doc_link_id=10.5794%2Fjjoms.66.553&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.66.553&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)  

Although emergence of keratin 17 (K17) and reciprocal loss of K13 are immunohistochemical hallmarks for oral mucosal malignancy, we report here findings of K17-positive (+) speckles, possibly equivalent to Civatte bodies, in benign oral lichen planus. Sixty-two biopsy samples from oral lichen planus cases were subjected to immunohistochemical examinations to analyze the distribution as well as histopathogenesis of Civatte bodies. K17 was irregularly positive among oral lichen planus-affected epithelial cells, and K17-positive (+) filamentous structures were irregularly distributed within the cytoplasm in confocal images. K17+ speckles were identified as Civatte bodies, and they were mainly distributed in the interface between epithelial cells and lymphocytic infiltrates (type A, 52.8%), followed by distribution within the epithelial layer (type B, 24.7%) or within the lamina propria with lymphocytic infiltration (type C, 22.5%). Apoptotic figures were often engulfed by macrophages and clearly distinguished from Civatte bodies by the presence TUNEL signals. These results indicate that K17 is a sensitive immunohistochemical marker for Civatte bodies and useful for differential diagnosis of oral lichen planus from other oral mucosal lesions. Civatte bodies are generated from denucleation of K17+ epithelial cells during the process of cell death via dyskeratosis, which is possibly related to blood capillary collapse.

DOI： 10.1038/s41598-020-71496-8

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Ectomesenchymal chondromyxoid tumour (ECT) is an extremely rare intraoral mesenchymal tumour. Most of these tumours have been identified on the anterior aspect of the dorsal surface of the tongue. ECT is difficult to diagnose because of its rarity. We report a case of ECT arising on the lateral border of the tongue in a 67-year-old woman. The tumour, measuring 20 × 10 mm in size, was surgically removed. Histopathologically, the tumour was composed of small polygonal cells arranged in sheets, with a myxoid or hyalinized stroma. The tumour boundary was clear; however, the tumour showed a multinodular structure expanding along the tongue surface without obvious capsule. Careful examination revealed the tumour nodule to be spreading in a skip lesion-like fashion away from the main part of the tumour in the striated muscle layer. Although there was no evidence of recurrence at 18 months after the surgery, our observations suggest that surgery for ECT resection with a safety margin is more appropriate than enucleation.

DOI： 10.1016/j.ijom.2020.04.010

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Language：Japanese   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Masseter muscle hypertrophy is defined as the unilateral or bilateral expansion of the masseter muscle, and little is known about its etiology. Here we report a case of masseter muscle hypertrophy in a female patient in her 20 s who complained of facial asymmetry. Because of the hemifacial overgrowth of the right-side maxillofacial region from birth, she was thought to have congenital hemifacial hyperplasia. After orthodontic treatment and osteotomy, the patient underwent debulking of the right masseter muscle. Histologically, the surgical specimens exhibited thick masseter muscle fibers arranged irregularly. Masseter muscle cells exhibited diameters in the range of 20-60 mu m.

DOI： 10.1016/j.ajoms.2019.08.005

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Methotrexate (MTX) is an antifolate that has been used as a chemotherapeutic agent for the treatment of neoplasm, such as leukemia and osteosarcoma. Moreover, MTX is also commonly used for treatment of chronic rheumatoid arthritis (RA). Here, we report a case of severe stomatitis in a patient with RA, which was caused by misuse of MTX. An 83-year-old female patient visited our department with the chief complaint of oral mucosal pain, accompanied by extreme fatigue. Severe stomatitis lesions were observed throughout her oral mucosa. Moreover, blood examination revealed pancytopenia. The patient reported a history of RA, and had been prescribed MTX since 2004. Although 6 mg MTX should be used twice per week, the patient mistakenly used MTX every day following her last consultation, for a period of 1 month. These findings led to a diagnosis of severe stomatitis, pancytopenia, and sepsis, all induced by misuse of MTX. Ultimately, she was treated with blood transfusion, antibiotics, and intravenous hyper alimentation, as well as administration of granulocyte colony-stimulating factor.MTX for the treatment of RA should be carefully managed to limit the risk of its misuse, especially in elderly patients, because of the severity and potential lethality of symptoms.

DOI： 10.1016/j.ajoms.2018.06.009

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© 2019 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.

DOI： 10.1016/j.ajoms.2018.07.010

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Language：Japanese   Publisher：(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 ¹⁸F-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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Salivary gland carcinomas (SGCs) exhibit heterogeneous biological behaviors, including the formation of distant metastases, which is a critical event associated with poor prognosis. Ezrin, which is a member of the ezrin-radixin-moesin family of plasma membrane cytoskeleton linker proteins, may provide a marker for metastasis and poor survival of patients with cancer. The aim of the present study was to investigate the relationship between ezrin expression and the expression of HER2, p53, and Ki-67 as well as dinicopathological factors in SGCs. For this purpose, we used immunohistochemistry to analyze the expression of these proteins in tissue microarrays prepared from formalin-fixed, paraffin-embedded primary tumor tissues of 221 patients with SGCs. Using receiver operating characteristic curves, we determined cut-off values of 30% and 5.0% for high expression of ezrin and Ki-67, respectively. High ezrin expression detected in samples from 63 (28.5%) patients with SGCs significantly correlated with male sex, high-grade histopathology, high Ki-67 labeling index, HER2 overexpression, aberrant expression of p53, and distant metastasis. Multivariate analysis demonstrated that high ezrin expression was an independent prognostic factor for shorter overall survival (hazard ratio, 2.11 [1.09-4.05]; P = .027). Furthermore, concomitant high expression of ezrin and HER2 overexpression correlated significantly with shorter disease-free survival and overall survival as well as a high incidence of distant metastasis (P &lt; .001). These findings indicate that ezrin and HER2 expression in patients with SGCs represents a high-grade histopathological subtype that requires adjuvant therapy, including molecularly targeted therapies, to decrease the risk of subsequent metastasis. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2017.02.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.yexmp.2017.02.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Cancer is often associated with dysregulation of both the humoral and cellular immune response, which in some instances is believed to result from changes in immune cell populations. For example, immunosuppressive CD11b(+)Gr-1(+) myeloid-derived suppressor cells have been shown to proliferate in the tumor microenvironment and surrounding tissues, highlighting the relationship between tumor growth and impairment of the immune response. However, the role of myeloid-derived suppressor cells in cancer progression has not been fully characterized because these cells are heterogeneous with properties influenced by the type and location of the tumor. Here, we show that CD11b(+)Gr-1(+) cells are elevated in the peripheral blood, spleen, and tumor of mice with oral squamous cell carcinoma. The phenotype and function of these cells varied depending on the tissue of origin. In particular, CD11b(+)Gr-1(+) cells in tumors expressed PD-L1 more abundantly than those in other tissues. Accordingly, CD11b(+)Gr-1(+) cells from tumors, but not from the spleen, suppressed T cell proliferation in vitro. The results suggest that tumor-derived or immune factors result in the accumulation of phenotypically and functionally diverse populations of CD11b(+)Gr-1(+) cells in mice with oral squamous cell carcinoma. The data also indicate that PD-L1 expression in CD11b(+)Gr-1(+) cells contributes to immune suppression, implying that targeting both myeloid-derived suppressor cells and PD-L1 would be an effective immunotherapeutic strategy against oral cancer. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2016.05.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.prp.2016.02.016

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1111/jop.12290

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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.

DOI： 10.1016/j.oooo.2015.04.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.humpath.2015.03.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1007/s00428-015-1735-6

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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.

DOI： 10.1007/s00418-014-1198-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1111/jop.12184

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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.

DOI： 10.1016/j.oooo.2013.08.032

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We present a preliminary case report on the application of computed tomography perfusion (CTP) with a single-compartment kinetic model for early detection of subsequent lymph node metastasis in gingival carcinoma. A 47-year-old female patient with squamous cell carcinoma of the right lower molar gingiva (cT1N0M0) was reviewed. At 4 months after the initial treatment, a subsequent lymph node metastasis was suspected on monthly follow-up ultrasonography. She provided written informed consent prior to participating in the study, which had been approved by the institutional review board at our institution. After a standard head and neck contrast-enhanced CT examination, CTP images were acquired with a coverage of 32 mm (64 x 0.5-mm thickness) and a total acquisition time of 45 s, initiated at 5 s after intravenous infusion of 40 ml of 370 mg I/ml non-ionic iodine contrast agent at a rate of 4 ml/s. Post-processing of the CTP data was performed with dedicated software based on a single-compartment kinetic model (Ziosoft Inc., Tokyo, Japan). The SC flow parameter represented the blood flow per unit volume of tissue, in milliliters per minute per milliliter (i.e., min(-1)). The mean SC flow value was 1.144 min(-1) in a totally replaced metastatic node and 0.985 min(-1) in a partially replaced node, compared with 0.787 min(-1) in the contralateral benign node. In conclusion, CTP with a single-compartment kinetic model is considered to be one of the useful methods for detection of a small non-necrotic subsequently developing metastatic cervical lymph node.

DOI： 10.1007/s11282-013-0153-1

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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.

DOI： 10.1016/j.humpath.2013.08.011

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IL-17RA, a member of the interleukin (IL)-17 receptor family, is a single membrane-spanning protein that ubiquitously expressed on the cell surface. IL-17RA transduces IL-17A, IL-17F, and IL-17A/F heterodimermediated signals by forming a complex with IL-17RC, and also signals the IL-17E (also known as IL-25) response in combination with IL-17RB (also known as IL-25R). Previously, soluble isoforms of human IL-17RC and IL-17RB have been reported, but the existence of a soluble isoform of human IL-17RA has remained unclear. Here, we report the identification of a soluble isoform of human IL-17RA at the mRNA and protein levels. Reverse transcribed PCR experiments showed that the IL-17RA variant is generated by spliced out of exon 11 encoding the transmembrane region in a variety of human tissues. The soluble IL-17RA isoform was detected in the culture media of human cell lines by Western blotting. The existence of the soluble IL-17RA isoform sheds new light on the regulation of IL-17RA mediated responses. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.cyto.2013.09.012

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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.

DOI： 10.1002/jcp.24364

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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.

DOI： 10.1038/labinvest.2013.86

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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.

DOI： 10.1016/j.ajoms.2012.12.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The significance of epidermal growth factor receptor (EGFR) signaling has been recognized in various cancers and anti-EGFR therapies in Japan are currently under consideration in squamous cell carcinoma of the head and neck (SCCHN) similar to colorectal cancer. However, there was no established survey regarding heterogeneous EGFR protein expression in Japanese SCCHN patients. The purpose of this study is to examine the relationship between EGFR expression or KRAS mutation (related to the alteration of EGFR pathway) and the clinicopathological characteristics of SCCHN.
We retrospectively examined the expression of EGFR protein by immunohistochemistry and KRAS gene mutation at codons 12 and 13 by using paraffin-embedded and formalin-fixed primary tumor tissues from 205 patients with SCCHN who underwent surgery at National Cancer Center Hospital East.
In 200 of the 205 patients (97.6 %), EGFR protein was expressed despite intratumoral heterogeneity. No patients had KRAS mutation at codons 12 or 13, and all 183 tumors showed wild-type KRAS. Positive rate of EGFR protein expression was significantly associated with better disease free survival (DFS) (P = 0.0471) and the intensity of EGFR protein expression showed a tendency for better DFS (P = 0.1034). Both higher EGFR positive rate and more intense EGFR expression were significantly associated with well differentiated subtype of squamous cell carcinoma (P = 0.0003 and P = 0.0007, respectively).
Most SCCHN patients may be good candidates for the anti-EGFR therapies.

DOI： 10.1007/s10147-012-0402-z

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Objective: The aim of this study is to characterize immunohistochemical profiles of lining epithelia of nasopalatine duct cyst (NPC) as well as to correlate those findings with their clinicopathological features to understand the histopathogenesis of NPC. Materials and methods: Forty-one surgical specimens from NPC were examined for clinical profiles and expression of keratin-7, 13, MUC-1, and P63 by immunohistochemistry, compared to radicular cyst (RC) and maxillary sinusitis. Results: Nasopalatine duct cyst was clinically characterized by male predominant occurrence: 44% of the cases involved tooth roots, and 70% with inflammatory backgrounds. Lining epithelia of NPCs without daughter cysts were immunohistochemically distinguished into three layers: a keratin 7-positive (+) ciliated cell layer in the surface, a keratin-13+ middle layer, and a MUC-1+/P63+ lower half, indicating that they were not respiratory epithelia, and the same layering pattern was observed in RC. However, those immunolocalization patterns of the main cyst lining with daughter cyst were exactly the same as those of daughter cyst linings as well as duct epithelia of mucous glands. Conclusions: Two possible histopathogeneses of NPC were clarified: one was inflammatory cyst like RC and the other was salivary duct cyst-like mucocele. © 2012 John Wiley &amp
Sons A/S.

DOI： 10.1111/odi.12022

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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.

DOI： 10.1016/j.bbrc.2013.03.057

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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.

DOI： 10.1007/s00428-012-1359-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.humpath.2012.02.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

DOI： 10.1038/modpathol.2011.218

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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.

DOI： 10.1007/s00428-012-1224-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aims: One of the important histopathological characteristics of oral epithelial dysplasia is a two-phase appearance of rete processes, comprising an upper layer of keratinized cells and a lower layer of basaloid cells, and thereby creating a sharp contrast between these two separate cell populations. The aim of this study was to determine the cellular adhesion status of the basaloid cells.
Methods and results: Immunohistochemistry for beta-catenin, E-cadherin and their related molecules was carried out in surgical specimens of two-phase epithelial dysplasia of the oral mucosa. The lower-half basaloid cells and the upper keratinized cells were microdissected separately, and extracted DNA samples were subjected to methylation-specific polymerase chain reaction amplification for E-cadherin. beta-Catenin was immunolocalized within the nuclei and cytoplasm of Ki67-positive lower-half basaloid cells, as well as on the cell membrane of upper parakeratotic cells. The basaloid cells of the lower-half were also positive for matrix metalloproteinase-7 and cyclin D1, beta-catenin target gene products, alpha-dystroglycan, tenascin-C, and perlecan, but not for E-cadherin. The promoter region of the E-cadherin gene was hypermethylated.
Conclusions: The solid proliferation of lower-half E-cadherin-free basaloid cells is enhanced by Wnt signalling cascades, as well as by the intraepithelial extracellular matrix or its bound growth factors.

DOI： 10.1111/j.1365-2559.2011.03929.x

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OBJECTIVES: The deposition of perlecan, a heparan sulfate proteoglycan, is enhanced within oral carcinoma in situ (CIS) foci, while it dynamically switches from CIS foci to the stromal space in squamous cell carcinoma (SCC). Because alpha-dystroglycan and integrin beta 1 have been identified as two of the perlecan receptors, we wanted to determine their differential distributions before and after invasion of oral SCC.
METHODS: Eighty-two surgical tissue specimens of oral SCC containing different precancerous stages were examined by immunohistochemistry for perlecan, alpha-dystroglycan, integrin beta 1, and Ki-67. In addition, alpha-dystroglycan mRNA signals were localized by in situ hybridization.
RESULTS: In normal epithelia, alpha-dystroglycan and integrin beta 1 were localized on the cell membrane of basal cells, while perlecan was faintly present in the intercellular spaces of parabasal cells. In epithelial dysplasia and CIS, alpha-dystroglycan and perlecan were well co-localized in the epithelial layer, especially in its lower half, and this co-localization was mostly overlapped with Ki-67-positive (+) cell zones. However, in SCC, alpha-dystroglycan was localized neither within carcinoma cell nests nor in the stroma, while perlecan disappeared from SCC foci but emerged in the stromal space, leaving integrin beta 1+ and Ki-67+ cells only to the periphery of SCC foci. alpha-Dystroglycan mRNA signals were basically identical to the alpha-dystroglycan protein localizations.
CONCLUSION: The findings suggest that alpha-dystroglycan and integrin beta 1 act as perlecan receptors in oral precancerous lesions prior to invasion, and that the perlecan signals via the two different receptors function in cellular differentiation and proliferation of CIS cells, respectively. J Oral Pathol Med (2010) 40: 552-559

DOI： 10.1111/j.1600-0714.2010.00990.x

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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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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. © 2010 International Association of Oral and Maxillofacial Surgeons.

DOI： 10.1016/j.ijom.2010.11.009

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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.

DOI： 10.1002/jemt.20900

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Objective. The objective of this study was to evaluate the inferior alveolar nerve (IAN) morphologically in patients with symptomatic posttraumatic sensory disorders using magnetic resonance imaging (MRI) on a high-field system.
Study design. Sixteen patients who complained of persistent sensory disturbance attributed to unilateral IAN injury participated in the investigation. High-resolution 3-dimensional volume rendering magnetic resonance neurography was performed on a 3.0-T MRI system.
Results. In 15 (94%) of 16 patients, high-resolution 3-dimensional volume rendering magnetic resonance neurography demonstrated morphologic abnormalities of the IAN as well as connective tissue overgrowth. These findings were confirmed intraoperatively (6 patients) and histopathologically (5 patients). The duration of sensory disturbance correlated significantly with the pattern of morphologic deformity and connective tissue overgrowth.
Conclusions. The current study clearly demonstrated that appropriate application of clinical MRI techniques can significantly improve the diagnosis and potential treatment of patients with orofacial peripheral nerve disorders. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:95-102)

DOI： 10.1016/j.tripleo.2010.09.002

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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.

DOI： 10.1111/j.1600-0714.2010.00938.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

DOI： 10.1159/000324926

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1111/j.1365-2559.2010.03712.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aims:
To examine the prognostic impact of geminin expression, a negative regulator of DNA replication, in salivary gland carcinomas.
Methods and results:
Tissues from 170 patients with salivary gland carcinoma were assembled in a tissue microarray format, and immunohistochemistry staining for geminin and Ki67 was performed. Patients were categorized into three groups using the tertile values of the labelling index (LI) for each marker as the cut-off points for constructing Kaplan-Meier survival curves. The LI for geminin was relatively low in acinic cell carcinoma (mean 1.55%) and mucoepidermoid carcinoma (mean 2.43%), intermediate in adenoid cystic carcinoma (mean 4.09%), and relatively high in salivary duct carcinoma (mean 15.22%). The geminin LI was significantly correlated with the Ki67 LI and histopathological factors, including pathological T factor, lymphatic and blood vessel infiltration, and lymph node metastasis. The increased expression of geminin was more strongly associated with reduced overall and relapse-free survival rates than with Ki67 expression and was a significant and independent prognostic factor in patient survival and tumour relapse.
Conclusions:
Geminin expression is potentially a useful marker for predicting tumour aggressiveness and clinical outcome in salivary gland carcinomas.

DOI： 10.1111/j.1365-2559.2010.03561.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Microvascular irregularities are associated with composition of squamous epithelial lesions and correlate with subepithelial invasion of superficial-type pharyngeal squamous cell carcinoma
Aims:
Superficial squamous epithelial lesions of the pharynx are increasingly recognized by architectural changes in the intraepithelial papillary capillary loop (IPCL) assessed by narrow-band imaging (NBI). The aim was to explore the histology of squamous epithelial precursor lesions and superficial-type pharyngeal squamous cell carcinoma (STPSCC), including squamous cell carcinoma (SCC) in situ and early invasive SCC, by focusing on microvascular irregularities to investigate the composition of those lesions and to explore the pathological characteristics of STPSCCs.
Methods and results:
Several pathological factors including thickness of intraepithelial squamous cell carcinoma (IESCC) and tumour thickness and microvascular density (MVD) were examined in 104 STPSCCs from 69 patients. The results show that architectural change of IPCL was recognized in precursor lesions in parallel with architectural disturbance and cytological atypia for criteria of diagnosing dysplasia. In 104 STPSCCs, the MVD of IESCC was correlated with the thickness of IESCC (P = 0.0115). Moreover, invasive SCC showed significantly higher MVD of IESCC (P = 0.0078) and there was significant correlation between the thickness of IESCC and subepithelial invasion (P &lt; 0.0001).
Conclusions:
Microvascular irregularities are an important pathological factor in carcinogenesis and early invasiveness of SCC of the pharynx.

DOI： 10.1111/j.1365-2559.2010.03512.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Advanced prostate cancer frequently involves the bone, where the insulin-like growth factor (IGF)-II is abundant. However, the importance of IGF-II in bone metastasis from prostate cancer is uncertain. The present study was aimed at examining the therapeutic importance of targeting IGF-II in bone metastases from prostate cancer.
Experimental Design: We investigated whether inhibiting IGF-II using a human neutralizing antibody (m610) suppresses the growth of prostate cancer cells in a human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of nonobese diabetic/severe combined immunodeficient mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody (m102.4) once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells.
Results: Histomorphologic examination indicated that m610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. m610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. m610 prevented the in vitro IGF-II-induced proliferation of MDA PCa 2b cells.
Conclusions: Our results indicate that IGF-II plays an important role in the prostate cancer cell growth in human bone, suggesting that targeting it by neutralizing antibodies offers a new therapeutic strategy for bone metastasis from prostate cancer. Clin Cancer Res; 16(1); 121-9. (C)2010 AACR.

DOI： 10.1158/1078-0432.CCR-09-0982

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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.

DOI： 10.1016/j.cancergencyto.2009.08.002

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Language：English   Publisher：日本癌学会  

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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. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2008.10.012

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Background: As one of the valuable tools for differential diagnoses of oral epithelial dysplasia, carcinoma in situ (CIS) and squamous cell carcinoma (SCC), we have proposed the immunohistochemistry for perlecan, a heparan sulfate proteoglycan (HSPG). As HSPGs have been shown to be extracellular docking molecules for matrix metalloproteinase (MMP) 7, our aim was to determine the expression mode of MMP-7 in these lesions for its possible diagnostic aid for oral borderline malignancies. Methods: Twenty cases each of moderate dysplasia, CIS, SCC, and normal/hyperplastic/mild dysplastic epithelia of the tongue and buccal mucosa were immunohistochemically examined for MMP-1, -2 and -7 in reference to their perlecan immunolocalization. Results: The expression of all three MMPs in the normal mucosal epithelium was restricted mainly to the parabasal layers. The most striking finding was strong expression of MMP-7 in epithelial dysplasia with a two-phase appearance: a clear demarcation of MMP-7-immunopositive (+) lower dysplastic/basaloid cells from non-positive upper keratinized cells. MMP-7+ cells were spread over the whole epithelial layer of CIS. In SCC, MMP-7 positivity was reduced from carcinoma cells but instead appeared in stromal cells. These expression profiles of MMP-7 resembled those of perlecan. MMP-1 and MMP-2 exhibited a similar but much weaker staining than MMP-7. Conclusion: These results suggest that the enhanced metabolism of perlecan associated with MMP-7 plays an important role in the cell proliferation of oral epithelia in their malignant transformation process, and that MMP-7 immunohistochemistry may be a valuable aid for identification of the cell proliferation center in oral CIS and dysplasia. © 2009 John Wiley &amp
Sons A/S.

DOI： 10.1111/j.1600-0714.2009.00750.x

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Background: 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. Methods: 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. Results: 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%). Conclusion: 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. © 2009 John Wiley &amp
Sons A/S.

DOI： 10.1111/j.1600-0714.2008.00742.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Purpose: The aim of this Study was to determine the prognostic value of expression of ATP binding cassette (ABC) transporter proteins and DNA repair gene Proteins by immunohistochemically staining tumor biopsy specimens from patients with advanced non-small-cell lung cancer (NSCLC) being treated with platinum-based chemotherapy.
Experimental design: Expression of ABC transporter proteins, including BCRP (breast cancer resistance protein) and MRP2 (multidrug resistance proteins 2), and the DNA-repair related proteins, ERCC1 (excision repair Cross-complementation group 1) and BRCA1 (breast cancer type 1 susceptibility protein) was assessed immunohistochemically in 156 tumor samples from untreated stage IV NSCLC patients. All of the patients had received platinum-based chemotherapy. Response to chemotherapy, progression-free Survival (PFS), and overall survival were compared in relation to expression of each of the proteins and to clinicopathological factors.
Results: High ERCC1 expression was associated with short survival (237 clays vs. 453 days, log-rank P=0.03), but not with response to chemotherapy or PFS. And high BCRP expression was associated with short survival (214 days vs. 412 days, log-rank P=0.02) but not with response to chemotherapy OF PFS. Multivariate analysis confirmed that negativity for the expression of BCRP tends to be an independent variable related to overall survival (P=0.06).
Conclusions: This study examined ERCC1 and BCRP expression in biopsy specimens as candidates for predictors of the survival of patients with advanced NSCLC treated with platinum-based chemotherapy. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2008.07.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant neoplasm that histologically resembles thymic carcinoma and arises in the thyroid gland or adjacent soft tissue of the neck. Herein is reported the case of a 62-year-old male patient with CASTLE exhibiting neuroendocrine differentiation, who was treated with total pharyngolaryngo-esophagectomy and total thyroidectomy. Gross examination of the surgical specimen showed a grayish-white, solid, lobulated tumor, mainly located between the trachea and esophagus, and involving the lower part of the left thyroid lobe. Histologically, the tumor consisted of epithelial cell nests separated by thick fibrous septa. The tumor cells were polygonal in shape, and contained pale cytoplasm and a vesicular nucleus with prominent nucleoli. There were few mitotic figures. Rosette-like arrangements that suggested neuroendocrine differentiation were observed in part of the tumor. The tumor cells were positive for CD5 and neuroendocrine markers including synaptophysin and chromogranin A.

DOI： 10.1111/j.1440-1827.2008.02310.x

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Language：Japanese  

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Language：Japanese   Publisher：Japanese Society of Oral and Maxillofacial Surgeons  

Osteoma in the maxillary sinus, especially isolated osteoma, is very rare in Japan. We present a case of isolated osteoma in the maxillary sinus that was detected by chance on cephalograms obtained before surgical orthodontic treatment to correct facial asymmetry. There were no signs or symptoms caused by the osteoma. After orthodontic treatment for 3 years, the tumor was removed simultaneously with Le Fort I osteotomy under general anesthesia. The tumor was encapsulated by fibrous tissue and was isolated from the maxillary sinus wall. It measured 28×14×12 mm. Histopathologically, the lesion was diagnosed as an osteoma. There has been no sign of recurrence for 3 years after surgery. Reports of Japanese cases of osteomas of the maxillary sinus are clinicopathologically reviewed.

DOI： 10.5794/jjoms.50.193

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Other Link： http://search.jamas.or.jp/link/ui/2004189735

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BACKGROUND: As perlecan contains a low-density lipoprotein (LDL) receptor-like repeats in the second domain of its core protein, LDL may be bound to perlecan, which is rich in granulation tissues. We wanted to study if this is the case in the cyst wall of radicular cysts, which are often associated with cholesterol granuloma. METHODS: Thirty-three specimens of radicular cyst with cholesterol granulomas were immunohistochemically examined for comparative localizations of perlecan, apoprotein B (apo B), and oxidized LDL (Ox-LDL), and for mRNA expression levels for perlecan. RESULTS: Myxoid or edematous stroma of immature granulation tissues was strongly positive for perlecan and simultaneously for apo B and Ox-LDL. Macrophages including foamy cells scattered in the granulation tissues were also immunopositive for Ox-LDL and occasionally for apo B. In situ hybridization showed that fibroblasts, endothelial cells, and pericytes had strong signals for perlecan, which was also confirmed by RT-PCR. CONCLUSION: These results suggest that perlecan, which is abundantly produced and accumulated in the cyst wall of immature granulation tissue, traps Ox-LDL locally, and that Ox-LDL is phagocytosed by macrophages. Thus, LDL-laden foamy macrophages are aggregated in the granulation tissue, and free cholesterol from ruptured macrophages may be concentrated locally to be crystallized, which may induce foreign body granulomas in the cyst wall.

DOI： 10.1111/j.0904-2512.2004.00087.x

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We report a case of odontogenic keratocyst with a respiratory epithelial lining and a malformed impacted tooth in the maxilla of a 39-year-old Japanese female who suffered from swelling symptoms for half a year. CT examinations revealed an air-filled cystic lesion with an impacted tooth crown in the maxillary bone which expanded to the nasal cavity as well as to the maxillary sinus. Histopathologically, the surgically removed cyst wall consisted of fibrous granulation tissue with a lining of parakeratinized squamous epithelium as well as ciliated pseudostratified epithelium and with retention of desquamated keratin materials in the lumen. The impacted tooth was malformed lacking a root portion. We discuss the frequency of respiratory epithelium in odontogenic keratocysts.

DOI： 10.1034/j.1600-0714.2003.00149.x

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：Churchill Livingstone  

DOI： 10.1016/j.ijom.2020.11.026

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Language：Japanese   Publisher：(一社)歯科基礎医学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCI LTD  

DOI： 10.1016/j.ejca.2015.06.039

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DOI： 10.1016/j.ijom.2011.06.022

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Because autonomous proliferating cancer cells are often exposed to hypoxic conditions, there must be an alternative metabolic pathway, such as autophagy, that allows them to obtain energy when both oxygen and glucose are depleted. We previously reported finding that autophagy actually contributes to cancer cell survival in colorectal cancers both in vitro and in vivo. Pancreatic cancer remains a devastating and poorly understood malignancy, and hypoxia in pancreatic cancers is known to increase their malignant potential. In the present study archival pancreatic cancer tissue was retrieved from 71 cases treated by curative pancreaticoduodenectomy. Autophagy was evaluated by immunohistochemical staining with anti-LC3 antibody, as LC3 is a key component of autophagy and has been used as a marker of autophagy. The results showed that strong LC3 expression in the peripheral area of pancreatic cancer tissue was correlated with a poor outcome (P = 0.0170) and short disease-free period (P = 0.0118). Two of the most significant correlations among the clinicopathological factors tested were found between the peripheral intensity level of LC3 expression and tumor size (P = 0.0098) or tumor necrosis (P = 0.0127). Activated autophagy is associated with pancreatic cancer cells, and autophagy is thought to be a response to factors in the cancer microenvironment, such as hypoxia and poor nutrient supply. This is the first study to report the clinicopathological significance of autophagy in pancreatic cancer.

DOI： 10.1111/j.1349-7006.2008.00893.x

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