2022/05/26 更新

写真a

イシグロ タツヤ
石黒 竜也
ISHIGURO Tatsuya
所属
医歯学総合病院 総合周産期母子医療センター 助教
職名
助教
外部リンク

学位

  • 医学 ( 2005年3月   新潟大学 )

経歴

  • 新潟大学   医歯学総合病院 総合周産期母子医療センター   助教

    2014年4月 - 現在

  • 新潟大学   医歯学総合病院 産科婦人科   特任助教

    2013年4月 - 2014年3月

 

論文

  • ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer 国際誌

    Yutaro Mori, Kaoru Yamawaki, Tatsuya Ishiguro, Kosuke Yoshihara, Haruka Ueda, Ai Sato, Hirokazu Ohata, Yohko Yoshida, Tohru Minamino, Koji Okamoto, Takayuki Enomoto

    STEM CELL REPORTS   13 ( 4 )   730 - 746   2019年10月

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

    Uterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

    DOI: 10.1016/j.stemcr.2019.08.015

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  • Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer 国際誌

    Kaoru Yamawaki, Tatsuya Ishiguro, Yutaro Mori, Kosuke Yoshihara, Kazuaki Suda, Ryo Tamura, Masayuki Yamaguchi, Masayuki Sekine, Katsunori Kashima, Masaya Higuchi, Masahiro Fujii, Koji Okamoto, Takayuki Enomoto

    CANCER SCIENCE   108 ( 4 )   632 - 640   2017年4月

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

    Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions inadvanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

    DOI: 10.1111/cas.13196

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  • Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications 国際誌

    Tatsuya Ishiguro, Hirokazu Ohata, Ai Sato, Kaoru Yamawaki, Takayuki Enomoto, Koji Okamoto

    CANCER SCIENCE   108 ( 3 )   283 - 289   2017年3月

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

    Recently, many types of in vitro 3-D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3-D culture methods aim to preserve the biological characteristics of original tumors better than conventional 2-D monolayer cultures, and include tumor-derived organoids, tumor-derived spheroids, organotypic multicellular spheroids, and multicellular tumor spheroids. The 3-D culture methods differ in terms of cancer cell sources, protocols for cell handling, and the required time intervals. Tumor-derived spheroids are unique because they are purposed for the enrichment of cancer stem cells (CSCs) or cells with stem cell-related characteristics. These spheroids are grown as floating spheres and have been used as surrogate systems to evaluate the CSC-related characteristics of solid tumors in vitro. Because eradication of CSCs is likely to be of clinical importance due to their association with the malignant nature of cancer cells, such as tumorigenicity or chemoresistance, the investigation of tumor-derived spheroids may provide invaluable clues to fight against cancer. Spheroid cultures have been established from cancers including glioma, breast, colon, ovary, and prostate cancers, and their biological and biochemical characteristics have been investigated by many research groups. In addition to the investigation of CSCs, tumor-derived spheroids may prove to be instrumental for a high-throughput screening platform or for the cultivation of CSC-related tumor cells found in the circulation or body fluids.

    DOI: 10.1111/cas.13155

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  • Establishment and Characterization of an In Vitro Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity 国際誌

    Tatsuya Ishiguro, Ai Sato, Hirokazu Ohata, Yoshinori Ikarashi, Ryou-u Takahashi, Takahiro Ochiya, Masayuki Yoshida, Hitoshi Tsuda, Takashi Onda, Tomoyasu Kato, Takahiro Kasamatsu, Takayuki Enomoto, Kenichi Tanaka, Hitoshi Nakagama, Koji Okamoto

    CANCER RESEARCH   76 ( 1 )   150 - 160   2016年1月

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

    The establishment of cancer stem-like cell (CSC) culture systems may be instrumental in devising strategies to fight refractory cancers. Inhibition of the Rho kinase ROCK has been shown to favorably affect CSC spheroid cultures. In this study, we show how ROCK inhibition in human serous ovarian cancer (SOC) cells can help establish a CSC system, which illuminates cancer pathophysiology and its treatment in this setting. In the presence of a ROCK kinase inhibitor, spheroid cultures of SOC cells expressed characteristic CSC markers including ALDH1A1, CD133, and SOX2, along with differentiation and tumorigenic capabilities in mouse xenograft models of human SOC. High expression levels of ALDH, but not CD133, correlated with spheroid formation CSC marker expression and tumor forming capability. In clinical specimens of SOC, high levels of ALDH1A1 correlated with advanced stage and poor prognosis. Pharmacologic or genetic blockade of ALDH blocked cell proliferation and reduced expression of SOX2, the genetic ablation of which abolished spheroid formation, whereas SOX2 overexpression inhibited ALDH1A1 expression and blocked spheroid proliferation. Taken together, our findings illustrated a new method to culture human ovarian CSC, and they defined a reciprocal regulatory relationship between ALDH1A1 and SOX2, which impacts ovarian CSC proliferation and malignant progression. (C)2015 AACR.

    DOI: 10.1158/0008-5472.CAN-15-0361

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  • Proposing a molecular classification associated with hypercoagulation in ovarian clear cell carcinoma. 国際誌

    Ryo Tamura, Kosuke Yoshihara, Koji Matsuo, Nozomi Yachida, Ai Miyoshi, Kotaro Takahashi, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kazuaki Suda, Tatsuya Ishiguro, Shujiro Okuda, Teiichi Motoyama, Hirofumi Nakaoka, Akira Kikuchi, Yutaka Ueda, Ituro Inoue, Takayuki Enomoto

    Gynecologic oncology   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Although ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear. MATERIALS AND METHODS: We retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status. RESULTS: In the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways. CONCLUSIONS: CCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation.

    DOI: 10.1016/j.ygyno.2021.08.009

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  • Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance. 国際誌

    Kaoru Yamawaki, Yutaro Mori, Hiroaki Sakai, Yusuke Kanda, Daisuke Shiokawa, Haruka Ueda, Tatsuya Ishiguro, Kosuke Yoshihara, Kazunori Nagasaka, Takashi Onda, Tomoyasu Kato, Tadashi Kondo, Takayuki Enomoto, Koji Okamoto

    Cancer letters   521   29 - 38   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.

    DOI: 10.1016/j.canlet.2021.08.018

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  • The New Era of Three-Dimensional Histoarchitecture of the Human Endometrium. 国際誌

    Manako Yamaguchi, Kosuke Yoshihara, Nozomi Yachida, Kazuaki Suda, Ryo Tamura, Tatsuya Ishiguro, Takayuki Enomoto

    Journal of personalized medicine   11 ( 8 )   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The histology of the endometrium has traditionally been established by observation of two-dimensional (2D) pathological sections. However, because human endometrial glands exhibit coiling and branching morphology, it is extremely difficult to obtain an entire image of the glands by 2D observation. In recent years, the development of three-dimensional (3D) reconstruction of serial pathological sections by computer and whole-mount imaging technology using tissue clearing methods with high-resolution fluorescence microscopy has enabled us to observe the 3D histoarchitecture of tissues. As a result, 3D imaging has revealed that human endometrial glands form a plexus network in the basalis, similar to the rhizome of grass, whereas mouse uterine glands are single branched tubular glands. This review summarizes the relevant literature on the 3D structure of mouse and human endometrium and discusses the significance of the rhizome structure in the human endometrium and the expected role of understanding the 3D tissue structure in future applications to systems biology.

    DOI: 10.3390/jpm11080713

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  • Biological significance of KRAS mutant allele expression in ovarian endometriosis. 国際誌

    Nozomi Yachida, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Haruka Ueda, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Hiroaki Kase, Teiichi Motoyama, Takayuki Enomoto

    Cancer science   112 ( 5 )   2020 - 2032   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation-specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin-fixed paraffin-embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild-type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild-type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild-type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.

    DOI: 10.1111/cas.14871

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  • PET/MR imaging for the evaluation of cervical cancer during pregnancy. 国際誌

    Tatsuya Ishiguro, Nobumichi Nishikawa, Shiro Ishii, Kosuke Yoshihara, Kazufumi Haino, Masayuki Yamaguchi, Sosuke Adachi, Takafumi Watanabe, Shu Soeda, Takayuki Enomoto

    BMC pregnancy and childbirth   21 ( 1 )   288 - 288   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Malignancy during pregnancy is increasing, and the most common type of malignancy is uterine cervical cancer. When planning the treatment of cervical cancer, it is important to look for signs of metastasis before surgery, especially metastasis to the lymph nodes. In this report, we assessed the diagnostic value of positron emission tomography/magnetic resonance imaging (PET/MRI) for evaluating cervical cancer propagation before surgery, with a focus on pregnant women. CASE PRESENTATION: 18F Fluorodeoxyglucose (FDG)-PET/MRI was performed in seven pregnant cervical cancer patients (28-34 years old) at 9-18 gestational weeks. In case #5, a second PET/MRI was performed at 24 gestational weeks. Of seven FDG-PET/MRI examination series in six cases (cases #1-6), FDG-PET/MR imaging could detect cervical tumors with abnormal FDG accumulation; these tumors were confirmed with a standardized uptake value max (SUV max) titer of 4.5-16. A second PET/MRI examination in case #5 revealed the same SUV max titer as the first examination. In these six imaging series (cases #1-5), there were no signs of cancer metastasis to the parametrium and lymph nodes. However, in case #6, abnormal FDG accumulation in the left parametrial lymph nodes was also detectable. Pathological examination showed lymph node metastasis in case #6. In case #7, PET/MRI could not detect any abnormal FDG accumulation in the cervix and other sites. Cone biopsy demonstrated only micro-invasive squamous cell carcinoma. After treatment for cervical cancer, all seven patients have had no recurrence of disease within the follow-up period (2.8-5.6 years), and their children have developed appropriately. CONCLUSION: PET/MRI is an effective imaging tool to evaluate cervical cancer progression in pregnancy.

    DOI: 10.1186/s12884-021-03766-w

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  • Three-dimensional understanding of the morphological complexity of the human uterine endometrium

    Manako Yamaguchi, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Nozomi Yachida, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Teiichi Motoyama, Yu Watanabe, Shujiro Okuda, Kazuki Tainaka, Takayuki Enomoto

    iScience   24 ( 4 )   102258 - 102258   2021年4月

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

    DOI: 10.1016/j.isci.2021.102258

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  • Establishment of in vitro 3D spheroid cell cultivation from human gynecologic cancer tissues. 国際誌

    Haruka Ueda, Yutaro Mori, Kaoru Yamawaki, Tatsuya Ishiguro, Hirokazu Ohata, Ai Sato, Kentaro Sugino, Nozomi Yachida, Manako Yamaguchi, Kazuaki Suda, Ryo Tamura, Kosuke Yoshihara, Koji Okamoto, Takayuki Enomoto

    STAR protocols   2 ( 1 )   100354 - 100354   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable in vitro 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).

    DOI: 10.1016/j.xpro.2021.100354

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  • Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-like Cells using the Three-dimensional Co-culture System, NICO-1. 国際誌

    Yuko Miyagawa, Kazunori Nagasaka, Kaoru Yamawaki, Yutaro Mori, Tatsuya Ishiguro, Kei Hashimoto, Ryoko Koike, Siho Fukui, Takeru Sugihara, Takayuki Ichinose, Haruko Hiraike, Koichiro Kido, Koji Okamoto, Takayuki Enomoto, Takuya Ayabe

    Journal of visualized experiments : JoVE   ( 166 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer stem cells (CSCs) reside in a supportive niche, constituting a microenvironment comprised of adjacent stromal cells, vessels, and extracellular matrix. The ability of CSCs to participate in the development of endothelium constitutes an important characteristic that directly contributes to the general understanding of the mechanisms of tumorigenesis and tumor metastasis. The purpose of this work is to establish a reproducible methodology to investigate the tumor-initiation capability of ovarian cancer stem cells (OCSCs). Herein, we examined the neovascularization mechanism between endothelial cells and OCSCs along with the morphological changes of endothelial cells using the in vitro co-culture model NICO-1. This protocol allows visualization of the neovascularization step surrounding the OCSCs in a time course manner. The technique can provide insight regarding the angiogenetic properties of OCSCs in tumor metastasis.

    DOI: 10.3791/61751

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  • ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis 国際誌

    Nozomi Yachida, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Haruka Ueda, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Masanori Isobe, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    SCIENTIFIC REPORTS   10 ( 1 )   14260 - 14260   2020年8月

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

    ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

    DOI: 10.1038/s41598-020-71273-7

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  • 卵巣卵黄嚢腫瘍に対する妊孕性温存治療後、残存卵巣に発症した成熟嚢胞性奇形腫摘出術前に卵子凍結を施行した1例(A case of mature teratoma in the residual ovary after fertility-sparing therapy for ovarian yolk sac tumor managed with oocyte cryopreservation followed by cystectomy)

    茅原 誠, 安達 聡介, 鈴木 久美子, 石黒 竜也, 西川 伸道, 関根 正幸, 荒井 勇樹, 木下 義晶, 榎本 隆之

    Journal of Mammalian Ova Research   37 ( 1 )   43 - 49   2020年7月

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    記述言語:英語   出版者・発行元:(一社)日本卵子学会  

    症例は17歳.10歳時に卵黄嚢腫瘍IIICを発症し,右付属器切除と術後化学療法が施行された.初回治療から7年後,残存左卵巣に16cm大の成熟嚢胞性奇形腫が疑われた.正常卵巣部位は画像診断で非常に小さく明らかでなかった.卵巣腫瘍摘出術を施行した場合,医原性卵巣機能不全の発症を危惧したため,腫瘍摘出前に卵子凍結保存を施行する方針とした.性交歴がない事,経腔・経腹採卵では腫瘍内容液漏出の可能性があったため,予定開腹手術時に同期して採卵する方針とした.黄体期ランダムスタートとして,排卵誘発を施行し,hCGとGnRHアゴニスト併用によるダブルトリガー後に採卵した.計10個のMII卵を回収し,同日凍結保存した.卵巣腫瘍が非常に大きい場合,開腹卵巣腫瘍直視下で超音波ガイド下に採卵することは安全かつ有効である.(著者抄録)

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  • XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary 国際誌

    Ryo Tamura, Kosuke Yoshihara, Hirofumi Nakaoka, Nozomi Yachida, Manako Yamaguchi, Kazuaki Suda, Tatsuya Ishiguro, Koji Nishino, Hiroshi Ichikawa, Keiichi Homma, Akira Kikuchi, Yutaka Ueda, Yuji Takei, Hiroyuki Fujiwara, Teiichi Motoyama, Shujiro Okuda, Toshifumi Wakai, Ituro Inoue, Takayuki Enomoto

    ONCOGENE   39 ( 17 )   3541 - 3554   2020年4月

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

    Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

    DOI: 10.1038/s41388-020-1237-0

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  • Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients. 国際誌

    Kentaro Sugino, Ryo Tamura, Hirofumi Nakaoka, Nozomi Yachida, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Tatsuya Ishiguro, Sosuke Adachi, Masanori Isobe, Masayuki Yamaguchi, Katsunori Kashima, Teiichi Motoyama, Ituro Inoue, Kosuke Yoshihara, Takayuki Enomoto

    Scientific reports   9 ( 1 )   17808 - 17808   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

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  • Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium 国際誌

    Kazuaki Suda, Hirofumi Nakaoka, Kosuke Yoshihara, Tatsuya Ishiguro, Sosuke Adachi, Hiroaki Kase, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    HUMAN REPRODUCTION   34 ( 10 )   1899 - 1905   2019年10月

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

    STUDY QUESTION: Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium?SUMMARY ANSWER: Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium.WHAT IS KNOWN ALREADY: Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS).STUDY DESIGN, SIZE, DURATION: We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center.PARTICIPANTS/MATERIALS, SETTING, METHODS: The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometnum, endometriosis-related ovarian cancer and endometrial cancer.MAIN RESULTS AND THE ROLE OF CHANCE: Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 x 10(-11)) and normal endometrium (P = 1.4 x 10(-7)).LIMITATIONS, REASONS FOR CAUTION: The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear.WIDER IMPLICATIONS OF THE FINDINGS: Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma.

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  • Ectopic pregnancy following oral levonorgestrel emergency contraception use 国際誌

    Yohei Kitani, Tatsuya Ishiguro, Akiko Kobayashi, Ryo Tamura, Haruka Ueda, Sosuke Adachi, Nobumichi Nishikawa, Masayuki Sekine, Takayuki Enomoto

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   45 ( 2 )   473 - 476   2019年2月

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

    Levonorgestrel is used worldwide as an emergency oral contraceptive. There have been occasional reports of ectopic pregnancy after oral levonorgestrel use. We present a case of ectopic tubal pregnancy after the use of oral levonorgestrel as an emergency contraceptive in a 37-year-old woman with a history of treatment for Chlamydia trachomatis infection. She conceived after sexual intercourse on menstrual day 14 of the first menstrual cycle following a normal delivery. After salpingectomy for this right tubal pregnancy, her following pregnancy was an ectopic pregnancy in the contralateral tube, which was treated with laparoscopic salpingectomy. Histopathological examination revealed endometriosis. We should be aware of ectopic pregnancy even after emergency contraceptive use, especially in patients with risk factors, such as Chlamydia infection and endometriosis. Because the efficacy of levonorgestrel decreases after ovulation, we should check the stage of the cycle before prescription.

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  • Myomectomy scar ectopic pregnancy following a cryopreserved embryo transfer

    Tatsuya Ishiguro, Kaoru Yamawaki, Makoto Chihara, Nobumichi Nishikawa, Takayuki Enomoto

    REPRODUCTIVE MEDICINE AND BIOLOGY   17 ( 4 )   509 - 513   2018年10月

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

    CaseA 40year old woman with a history of a myomectomy visited the Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan, following 2years of infertility. Magnetic resonance imaging detected an abnormal endometrial-like pseudo-cavity. A hysterosalpingography also revealed an abnormal accumulation of contrast medium at the myometrial scar site. A transvaginal ultrasound showed a thin myometrium at the lower uterine body. The patient conceived via in vitro fertilization under a luteal phase down-regulation protocol (long protocol) for controlled ovarian stimulation, followed by a cryopreserved embryo transfer during her natural ovulation cycle. After the embryo transfer, the gestational sac was located at the subserosal site of the myomectomy scar.OutcomeConclusionAn emergent laparoscopic operation was performed and the embryo was removed successfully via laparoscopy under transvaginal ultrasonography.A subserosal uterine pregnancy is a rare form of intramural pregnancy, which is a rare subtype of an ectopic pregnancy, which could occur at the myomectomy site, especially after an embryo transfer. It is believed that this rare ectopic pregnancy resulted from embryo implantation under the serosa through a micro-sinus tract that was a site of suture failure of the myomectomy scar and was partially affected by the embryo transfer. Clinicians should consider the possibility of an ectopic pregnancy after uterine surgery, including a myomectomy.

    DOI: 10.1002/rmb2.12212

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  • Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium 国際誌

    Kazuaki Suda, Hirofumi Nakaoka, Kosuke Yoshihara, Tatsuya Ishiguro, Ryo Tamura, Yutaro Mori, Kaoru Yamawaki, Sosuke Adachi, Tomoko Takahashi, Hiroaki Kase, Kenichi Tanaka, Tadashi Yamamoto, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    CELL REPORTS   24 ( 7 )   1777 - 1789   2018年8月

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

    Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

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  • The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy 国際誌

    Kosuke Yoshihara, Tatsuya Ishiguro, Makoto Chihara, Eiri Shima, Sosuke Adachi, Masanori Isobe, Kazufumi Haino, Masayuki Yamaguchi, Masayuki Sekine, Katsunori Kashima, Koichi Takakuwa, Nobumichi Nishikawa, Takayuki Enomoto

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   28 ( 4 )   782 - 787   2018年5月

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

    Objectives Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies.Methods/Materials A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups.Results A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group.Conclusions Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby.

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  • Microdissection testicular sperm extraction in five Japanese patients with non-mosaic Klinefelter's syndrome

    Makoto Chihara, Kanna Ogi, Tatsuya Ishiguro, Kunihiko Yoshida, Chikako Godo, Koichi Takakuwa, Takayuki Enomoto

    REPRODUCTIVE MEDICINE AND BIOLOGY   17 ( 2 )   209 - 216   2018年4月

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

    CasesMicrodissection testicular sperm extraction (micro-TESE) was performed on five Japanese men with non-mosaic Klinefelter's syndrome (KS) and non-obstructive azoospermia in the authors' department. Here is reported the operative results and partner's clinical course for two cases where spermatozoa could be acquired. Also encountered was a man with non-mosaic KS with the partial deletion of azoospermia factor (AZF)b. Because this is rare, it is reported in detail in the context of the previous literature. This case series describes the first experience of micro-TESE by gynecologists in the current department.OutcomeThe egg collection date was adjusted to the micro-TESE day by using the modified ultra-long method. Intracytoplasmic sperm injection (ICSI) was implemented for two men whose spermatozoa were acquired by micro-TESE, with these progressing to the blastocyst stage. Subsequently, one case conceived after the transfer of fresh embryos and a healthy baby was delivered. However, spermatozoa could not be retrieved from the man with non-mosaic KS who was harboring the partial deletion of AZFb.ConclusionThese findings suggest that ovulation induction by using the modified ultra-long method with micro-TESE and ICSI on the same day represents an effective treatment option for men with non-mosaic KS. As there are cases where AZF deletion is recognized among patients with non-mosaic KS, screening before micro-TESE is strongly recommended.

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  • Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions. 国際誌

    Ryo Tamura, Kosuke Yoshihara, Tetsuya Saito, Ryosuke Ishimura, Juan Emmanuel Martínez-Ledesma, Hu Xin, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Seiya Sato, Hiroaki Itamochi, Teiichi Motoyama, Yoichi Aoki, Shujiro Okuda, Cristine R Casingal, Hirofumi Nakaoka, Ituro Inoue, Roel G W Verhaak, Masaaki Komatsu, Takayuki Enomoto

    Oncogenesis   7 ( 1 )   4 - 4   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

    DOI: 10.1038/s41389-017-0018-2

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  • Fetiform teratoma was a parthenogenetic tumor arising from a mature ovum 国際誌

    Kiyonori Miura, Takumi Kurabayashi, Chisei Satoh, Kensaku Sasaki, Tatsuya Ishiguro, Koh-ichiro Yoshiura, Hideaki Masuzaki

    JOURNAL OF HUMAN GENETICS   62 ( 9 )   803 - 808   2017年9月

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

    The aim of this study was to investigate the parthenogenetic origin of fetiform teratoma by using molecular genetic studies and methylation status analyses. A fetiform teratoma was removed from a 35-year-old nulligravida woman. Genotyping of microsatellite marker loci, microarray analysis of single-nucleotide polymorphism (SNP) loci and methylation status analysis of the differentially methylated region (DMR) within the human IGF2-H19 locus were performed. Karyotypes of the host and the fetiform teratoma were 46, XX. The fetiform teratoma was homozygous at all loci and meiotic recombinations in the tumor were confirmed by SNP microarray analysis. Methylation analysis indicated that the host had both methylated and unmethylated IGF2-H19 DMR alleles, while the fetiform teratoma had unmethylated alleles only. Genetically, the fetiform teratoma had homozygous genotypes with meiotic recombination and a duplicated unmethylated host allele, indicating that it was a parthenogenetic tumor arising from a mature ovum after meiosis II. This is the first demonstration of a fetiform teratoma originating from a mature haploid ovum.

    DOI: 10.1038/jhg.2017.45

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  • Recurrent ovarian undifferentiated carcinoma resembling hepatoid morphology treated with pegylated liposomal doxorubicin and bevacizumab 国際誌

    Tatsuya Ishiguro, Kastunori Kashima, Nozomi Yachida, Teiichi Motoyama, Takayuki Enomoto

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   43 ( 5 )   957 - 961   2017年5月

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

    Hepatoid carcinomas are undifferentiated epithelial carcinomas that are pathologically similar to hepatocellular carcinoma, but occur in a variety of organs. Hepatoid carcinomas, as strictly defined, typically produce a-fetoprotein. In addition, a standard effective chemotherapy regimen for hepatoid carcinoma has yet to be established. We present a case of advanced primary ovarian cancer that was pathologically similar to hepatoid carcinoma without staining for a-fetoprotein or hepatocyte paraffin 1. The primary ovarian, metastatic, and recurrent tumors shared similar pathological characteristics. Fourth-line chemotherapy with pegylated liposomal doxorubicin and bevacizumab was effective in treating the recurrent tumor, even though this disease had recurred three times.

    DOI: 10.1111/jog.13298

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  • Biochemical analysis of intraplacental choriocarcinoma and fetomaternal transfusion 国際誌

    Tatsuya Ishiguro, Kazuaki Suda, Takayuki Enomoto

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   43 ( 3 )   587 - 591   2017年3月

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

    Intraplacental choriocarcinoma is one of the rarest forms of gestational tumors and is believed to be one of the causes of fetomaternal transfusion (FMT). A 35-year-old woman, gravida 2, para 2, with a history of two vaginal deliveries, was incidentally diagnosed as having stage I gestational intraplacental choriocarcinoma with a FIGO/World Health Organization 2000 risk score of 2 after term delivery. This disease caused neonatal anemia but did not metastasize to either the mother or infant. Short tandem repeat analysis with laser microdissection revealed that the tumor had originated from the current pregnancy. Serological test and immunohistochemical analysis revealed that the patient and her baby suffered from FMT. She has been free from disease without any medical intervention for the last 1 year. A combination of multiple biochemical analyses might help us diagnose the precursor pregnancy of a gestational choriocarcinoma and FMT.

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  • Gestational choriocarcinoma: Rare spinal metastasis during a viable pregnancy 国際誌

    Tatsuya Ishiguro, Takehiro Serikawa, Tetsuro Yahata, Takayuki Enomoto

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   43 ( 2 )   421 - 424   2017年2月

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

    Gestational choriocarcinoma metastasizing to the bones, especially to the spine, is extremely rare. In addition, there are few reports of choriocarcinoma during a viable pregnancy. We report a case of gestational choriocarcinoma that metastasized to the lumbar spine during a viable pregnancy in a 41-year-old woman with a history of a missed abortion. A heterogeneous cervical mass was detected at gestational week 16. Subsequently, a metastatic lesion appeared during the pregnancy, and fetal demise in utero occurred. Pathological examination revealed that the cervical tumor and metastatic spinal tumor were choriocarcinoma. The patient's condition deteriorated rapidly and we were unable to save her life, despite multidrug chemotherapy. Surgical tumor resection and pregnancy might involve a substantial risk of choriocarcinoma metastasis. It is important to obtain an early diagnosis for this life-threatening disease in order to facilitate appropriate treatment, despite pregnancy.

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  • Abnormal bending of the umbilical cord due to adhesion of the cord to the placenta

    Tatsuya Ishiguro, Takao Ishiguro

    CLINICAL AND EXPERIMENTAL OBSTETRICS & GYNECOLOGY   44 ( 5 )   787 - 788   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:I R O G CANADA, INC  

    Background: Although cord abnormalities can cause fetal distress, there are many cases of fetal distress caused by unknown factors. Case: The mother was a 27-year-old Japanese woman. The umbilical cord was attached to nearly the center of the placenta, which was smoothly delivered. Macroscopically, at the site of cord attachment to the placenta, the cord appeared partially flattened and adhered to the placenta, resulting in abnormal bending of the cord. Pathological examination of the cord and placenta, including the site of adhesion, did not show any remarkable findings. Therefore, the adhesion might have caused temporary bending of the cord, which resulted in fetal distress. Conclusion: The authors encountered a rare case of abnormal adhesion of the umbilical cord to the placenta that caused fetal distress. The presence of abnormalities of the placenta and umbilical cord should be macroscopically examined immediately after delivery, even when only mild fetal distress is noted.

    DOI: 10.12891/ceog3727.2017

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  • Association of NR3C1/Glucocorticoid Receptor gene SNP with azoospermia in Japanese men 国際誌

    Makoto Chihara, Kosuke Yoshihara, Tatsuya Ishiguro, Sosuke Adachi, Hiroyuki Okada, Katsunori Kashima, Takaaki Sato, Atsushi Tanaka, Kenichi Tanaka, Takayuki Enomoto

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   42 ( 1 )   59 - 66   2016年1月

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

    AimThe molecular pathogenesis of non-obstructive azoospermia (NOA) is unclear. Our aim was to identify the genetic susceptibility for NOA in Japanese men by using a combination of transcriptome network analysis and SNP genotyping.Material and MethodsWe searched for candidate genes using RNA transcriptome network analysis of 2611 NOA-related genes that we had previously reported. We analyzed candidate genes for disease linkage with single nucleotide polymorphisms (SNP) in the genomes of 335 Japanese men with NOA and 410 healthy controls using SNP-specific real-time polymerase chain reaction TaqMan assays.ResultsThree candidate genes (NR3C1, YBX2, and BCL2) were identified by the transcriptome network analysis, each with three SNP. Allele frequency analysis of the nine SNP indicated a significantly higher frequency of the NR3C1 rs852977 G allele in NOA cases compared with controls (corrected P = 5.7e-15; odds ratio = 3.20; 95% confidence interval, 2.40-4.26). The other eight candidate polymorphisms showed no significant association.ConclusionThe NR3C1 rs852977 polymorphism is a potential marker for genetic susceptibility to NOA in Japanese men. Further studies are necessary to clarify the association between the NR3C1 polymorphism and alterations of glucocorticoid signaling pathway leading to male infertility.

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  • Novel kinase fusion transcripts found in endometrial cancer. 国際誌

    Ryo Tamura, Kosuke Yoshihara, Kaoru Yamawaki, Kazuaki Suda, Tatsuya Ishiguro, Sosuke Adachi, Shujiro Okuda, Ituro Inoue, Roel G W Verhaak, Takayuki Enomoto

    Scientific reports   5   18657 - 18657   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.

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  • Susceptibility to male infertility: replication study in Japanese men looking for an association with four GWAS-derived loci identified in European men 国際誌

    Makoto Chihara, Kosuke Yoshihara, Tatsuya Ishiguro, Yuki Yokota, Sosuke Adachi, Hiroyuki Okada, Katsunori Kashima, Takaaki Sato, Atsushi Tanaka, Kenichi Tanaka, Takayuki Enomoto

    JOURNAL OF ASSISTED REPRODUCTION AND GENETICS   32 ( 6 )   903 - 908   2015年6月

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

    A previous genome-wide association study in European men identified four single nucleotide polymorphism (SNP) loci associated with male infertility. Our aim was to replicate, if possible, the association of these SNPs with Japanese male infertility.We genotyped four SNPs (rs5911500, rs10246939, rs2059807, and rs11204546) in 517 Japanese patients with male infertility and 369 fertile controls using SNP-specific real-time polymerase chain reaction TaqMan assays. Subsequently, we divided patients with male infertility into azoospermia (n = 417) and oligospermia subgroups (n = 70).The four SNPs previously identified in European men showed no significant association with collective male infertility in our Japanese cohort. However, allele frequency analysis did indicate a significantly higher frequency of the rs11204546 C allele of the OR2W3 gene in the oligospermia subset of infertility patients compared with controls (p = 0.0037; odds ratio = 1.74; 95 % confidence interval, 1.21-2.53).Although this study was somewhat limited by overall sample size, the OR2W3 gene polymorphism rs11204546 was significantly associated with oligospermia in Japanese men, suggesting that OR2W3 might be involved in genetic susceptibility to Japanese male infertility as well as in European males.

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  • Induction of the Stem-like Cell Regulator CD44 by Rho Kinase Inhibition Contributes to the Maintenance of Colon Cancer-Initiating Cells 国際誌

    Hirokazu Ohata, Tatsuya Ishiguro, Yuki Aihara, Ai Sato, Hiroaki Sakai, Shigeki Sekine, Hirokazu Taniguchi, Takayuki Akasu, Shin Fujita, Hitoshi Nakagama, Koji Okamoto

    CANCER RESEARCH   72 ( 19 )   5101 - 5110   2012年10月

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

    The difficulty in expanding cancer-initiating cells in vitro is one of major obstacles for their biochemical characterization. We found that Rho kinase (ROCK) inhibitors as well as blebbistatin, a myosin II inhibitor, greatly facilitated the establishment of spheroids from primary colon cancer. The spheroid cells expressed cancer stem cell markers, showed the ability to differentiate, and induced tumors in mice. The spheroids were composed of cells that express various levels of CD44, whereas CD44(high) cells were associated with increased sphere-forming ability, expression of the activating form of beta-catenin, and elevated levels of glycolytic genes, CD44(-/low) cells showed increased levels of differentiation markers and apoptotic cells. The spheroid cells expressed variant forms of CD44 including v6, and the induction of the variants was associated with the activating phosphorylation of c-Met. As expected from the predicted hierarchy, CD44(high) cells differentiated into CD44(-/low) cells. Unexpectedly, a fraction of CD44(-/low) cells generated CD44(high) cells, and the ROCK inhibitor or blebbistatin primed the transition by inducing CD44 expression. We propose that the transition from CD44(-/low) to CD44(high) state helps to maintain a CD44(high) fraction and the tumorigenic diversity in colon cancer. Cancer Res; 72(19); 5101-10. (C) 2012 AACR.

    DOI: 10.1158/0008-5472.CAN-11-3812

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  • miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver 国際誌

    Koji Okamoto, Tatsuya Ishiguro, Yutaka Midorikawa, Hirokazu Ohata, Masashi Izumiya, Naoto Tsuchiya, Ai Sato, Hiroaki Sakai, Hitoshi Nakagama

    EMBO JOURNAL   31 ( 7 )   1752 - 1763   2012年4月

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

    Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed 'dropout' screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493* were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493*, but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells. The EMBO Journal (2012) 31, 1752-1763. doi: 10.1038/emboj.2012.25; Published online 28 February 2012

    DOI: 10.1038/emboj.2012.25

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  • Differential expression of nanog1 and nanogp8 in colon cancer cells 国際誌

    Tatsuya Ishiguro, Ai Sato, Hirokazu Ohata, Hiroaki Sakai, Hitoshi Nakagama, Koji Okamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   418 ( 2 )   199 - 204   2012年2月

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

    Nanog, a homeodomain transcription factor, is an essential regulator for promotion of self-renewal of embryonic stem cells and inhibition of their differentiation. It has been demonstrated that nanog1 as well as nanogp8, a retrogene of nanog1, is preferentially expressed in advanced stages of several types of cancer, suggesting their involvement during cancer progression. Here, we investigated the expression of Nanog in well-characterized colon cancer cell lines. Expression of Nanog was detectable in 5 (HCT116, HT29, RKO, SW48, SW620) out of seven cell lines examined. RNA expression analyses of nanog1 and nanogp8 indicated that, while nanog1 was a major form in SW620 as well as in teratoma cells Tera-2, nanogp8 was preferentially expressed in HT29 and HCT116. In accordance with this, shRNA-mediated knockdown of nanog1 caused the reduction of Nanog in SW620 but not in HT29. Inhibition of Nanog in SW620 cells negatively affected cell proliferation and tumor formation in mouse xenograft. Biochemical subcellular fractionation and immunostaining analyses revealed predominant localization of Nanog in cytoplasm in SW620 and HT29, while it was mainly localized in nucleus in Tera-2. Our data indicate that nanog1 and nanogp8 are differentially expressed in colon cancer cells, and suggest that their expression contributes to proliferation of colon cancer cells. (C) 2012 Published by Elsevier Inc.

    DOI: 10.1016/j.bbrc.2011.10.123

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MISC

共同研究・競争的資金等の研究

  • 特異的代謝メカニズムを標的とした婦人科悪性腫瘍がん幹細胞の新規治療法の探索

    研究課題/領域番号:18K09250  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    石黒 竜也, 榎本 隆之

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

    子宮体がん幹細胞の維持に寄与する特異的な代謝メカニズムの解明を目的とし,我々が樹立した臨床検体由来の子宮体がんスフェロイド細胞において,がん幹細胞マーカーアルデヒド脱水素酵素ALDH活性差による細胞の区分を行った。子宮体がんスフェロイド細胞の系において,ALDH活性が子宮体がん幹細胞の機能的マーカーであることは立証している。
    マイクロアレイ法を用い,同細胞のALDH高活性細胞(ALDH-high細胞)とALDH低活性細胞(ALDH-low細胞)の発現差を網羅的に確認し,Gene set enrichment analysis (GSEA)で検証すると,解糖系遺伝子群の有意な変動が確認された。
    Flux analyzerを用いた解析で,解糖系のECAR値はALDH-high細胞で優位に高く,ミトコンドリアの酸化的リン酸化のOCR値はALDH-low細胞で優位に高かった。ALDH-high細胞にALDH阻害剤を投与すると,ECAR値は低下,OCR値は上昇した。またグルコースの取り込みおよび細胞内のグルコース量・乳酸値はALDH-high細胞で優位に高く,ALDH阻害剤添加でいづれの値も有意に低下した。またクグルコース非添加培養および解糖系阻害剤の2-デオキシ-D-グルコース(2-DG)の添加の両条件において,ALDH-high細胞の細胞増殖が優位に抑制された。以上より,ALDH活性が解糖系の維持に寄与していることが示され,結果として子宮体がん幹細胞の増殖促進に関与していることが考えられた。

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  • 卵巣がん・子宮体がん幹細胞のがん腫特異的制御機構の解明

    研究課題/領域番号:15K20132  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    石黒 竜也

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    新潟大学遺伝子倫理委員会の承認,および患者同意を取得後に,新潟大学医歯学総合病院で手術・処置を施行された婦人科悪性腫瘍患者さまの臨床検体(腫瘍・腹水)由来の3次元スフェロイド培養を行い,これまでに複数の卵巣がん・子宮体がん由来の細胞の安定培養に成功した。
    特に子宮体がんスフェロイド細胞についてはがん幹細胞マーカーとして知られる“X”の差により,腫瘍形成や細胞増殖の差異を認め,マーカー“X”の重要性が示された。

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  • ヒト卵巣がん幹細胞における幹細胞制御因子の役割の解析

    研究課題/領域番号:24791729  2012年4月 - 2014年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    石黒 竜也

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

    ヒト卵巣がん臨床検体を用い,血清を含まない浮遊条件下での培養系においてがん細胞のの安定培養を試みた。我々はスフェロイド細胞とよばれる特異な細胞形態を呈する細胞の安定的な培養に成功した。これらスフェロイド細胞は腫瘍形成能や自己複製能・分化能などのがん幹細胞性質を持つ事を確認した。また幹細胞因子の発現抑制により同細胞の増殖・生存が抑制された。
    一方で,分化誘導後の細胞も腫瘍の形成能が確認,分化誘導後の細胞を血清を含まない浮遊条件下での培養を行うと,スフェロイドの再形成を認め,幹細胞因子の再上昇を認めた。
    以上より,卵巣がんにおいてがん細胞の両方向性の変化(分化可塑性)が存在する事が示された。

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  • 位置情報を加味した単一細胞シークエンス解析による卵巣明細胞癌発症機序の解明

    研究課題/領域番号:20K21647  2020年7月 - 2022年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    榎本 隆之, 井ノ上 逸朗, 吉原 弘祐, 安達 聡介, 田村 亮, 石黒 竜也

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

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  • 正常子宮内膜ゲノム解析に基づいた子宮内膜症及び内膜症関連卵巣癌の発症機序の解明

    研究課題/領域番号:20H03821  2020年4月 - 2023年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    榎本 隆之, 井ノ上 逸朗, 吉原 弘祐, 安達 聡介, 石黒 竜也, 田村 亮

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    配分額:17940000円 ( 直接経費:13800000円 、 間接経費:4140000円 )

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  • 進化論モデルを用いた単一起源細胞から子宮癌肉腫への発生機序解明と治療法の開発

    研究課題/領域番号:17H04336  2017年4月 - 2020年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    榎本 隆之, 井ノ上 逸朗, 吉原 弘祐, 安達 聡介, 石黒 竜也

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

    今年度は、まず進化論モデルの有効性を検証するために、同一症例における正常子宮内膜・子宮内膜症・異型子宮内膜症・卵巣明細胞癌の連続的全エクソンシークエンスを施行した。遺伝子変異の頻度は、正常子宮内膜から子宮内膜症、異型内膜症、明細胞癌と進むにつれて減少していた。一方、遺伝子変異の変異アリル頻度は、正常子宮内膜から子宮内膜症、異型内膜症、明細胞癌と進展するにつれて増加していた。同定された遺伝子変異データを進化論モデルに当てはめることにより、正常子宮内膜では遺伝子変異が多様性を持って存在し、そのうち変異陽性内膜上皮が月経血逆流により腹腔内に移動後、卵巣に生着し、クローン性に増殖することで子宮内膜症を形成することが推察された。さらに、子宮内膜症上皮に癌関連遺伝子変異が蓄積していくことで、異型子宮内膜症、卵巣明細胞癌への進展することが推察され、ゲノムデータを利用した進化論的アプローチが発生起源の探索に有効であることが実証された。興味深いことに、進化論的アプローチにより、子宮内膜症から異型内膜症で留まる進化プロセスと、子宮内膜症から異型内膜症、卵巣明細胞癌へと進展する進化プロセスの2通りに進化が分かれることが明らかになった。
    また子宮癌肉腫のスフェロイド樹立を進めるとともに、子宮体癌スフェロイドの生物学的特徴を明らかにするためにin vitro/vivoで実験を行った。特に癌幹細胞のマーカーと一つとされているALDH1に注目し、子宮体癌スフェロイドをALDH1高発現細胞と低発現細胞にソートすると、明らかに細胞増殖・薬剤感受性・代謝産物プロファイルに違いがあることを同定している。

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  • 腫瘍内不均一性に基づいた抗がん剤耐性機構の打破

    研究課題/領域番号:15K15598  2015年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    榎本 隆之, 吉原 弘祐, 加嶋 克則, 関根 正幸, 石黒 竜也

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

    対象を婦人科悪性腫瘍とし、臨床検体からスフェロイド培養を実施し、合計卵巣癌5例、子宮体癌4例、子宮頸癌1例、子宮癌肉腫1例のスフェロイド樹立に成功した。次に幹細胞形質に関与するSex-determining region Y-box 2 (SOX2) 遺伝子に注目し、子宮体癌細胞株を用いてSOX2の機能解析を行った。SOX2発現は子宮体癌細胞株の細胞増殖に強く関与しており、細胞周期調節に影響していた。SOX2発現は類内膜癌の悪性度及び予後と関連し、SOX2高発現+p21低発現群では、統計学的に有意に予後不良であり、SOX2とp21が子宮体癌の予後分子マーカーになりうることを明らかにした。

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