Updated on 2022/03/29

写真a

 
YOKOI Akira
 
Organization
Nagoya University Hospital Obstetrics and Gynecology Assistant Professor
Graduate School
Graduate School of Medicine
Title
Assistant Professor

Degree 1

  1. 博士(医学) ( 2017.7   名古屋大学 ) 

Research Interests 3

  1. 腫瘍生物学

  2. Ovarian cancer

  3. リキッドバイオプシー

Research Areas 3

  1. Life Science / Tumor diagnostics and therapeutics

  2. Life Science / Tumor biology

  3. Life Science / Obstetrics and gynecology

 

Papers 45

  1. Aberrant activation of cell cycle-related kinases and the potential therapeutic impact of PLK1 or CHEK1 inhibition in uterine leiomyosarcoma.

    Yoshida K, Yokoi A, Yamamoto T, Hayashi Y, Nakayama J, Yokoi T, Yoshida H, Kato T, Kajiyama H, Yamamoto Y

    Clinical cancer research : an official journal of the American Association for Cancer Research     2022.3

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    DOI: 10.1158/1078-0432.CCR-22-0100

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  2. Significance of platinum distribution to predict platinum resistance in ovarian cancer after platinum treatment in neoadjuvant chemotherapy. International journal

    Kaname Uno, Nobuhisa Yoshikawa, Akira Tazaki, Shoko Ohnuma, Kazuhisa Kitami, Shohei Iyoshi, Kazumasa Mogi, Masato Yoshihara, Yoshihiro Koya, Mai Sugiyama, Satoshi Tamauchi, Yoshiki Ikeda, Akira Yokoi, Fumitaka Kikkawa, Masashi Kato, Hiroaki Kajiyama

    Scientific reports   Vol. 12 ( 1 ) page: 4513 - 4513   2022.3

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    Most patients with ovarian cancer experience recurrence and develop resistance to platinum-based agents. The diagnosis of platinum resistance based on the platinum-free interval is not always accurate and timely in clinical settings. Herein, we used laser ablation inductively coupled plasma mass spectrometry to visualize the platinum distribution in the ovarian cancer tissues at the time of interval debulking surgery after neoadjuvant chemotherapy in 27patients with advanced high-grade serous ovarian cancer. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum throughout the tumor and adjacent stroma. The type A patients treated post-surgery with platinum-based adjuvant chemotherapy showed significantly shorter periods of recurrence after the last platinum-based chemotherapy session (p = 0.020) and were diagnosed with "platinum-resistant recurrence". Moreover, type A was significantly correlated with worse prognosis (p = 0.031). Post-surgery treatment with non-platinum-based chemotherapy could be effective for the patients classified as type A. Our findings indicate that the platinum resistance can be predicted prior to recurrence, based on the platinum distribution; this could contribute to the selection of more appropriate adjuvant chemotherapy, which may lead to improves prognoses.

    DOI: 10.1038/s41598-022-08503-7

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  3. Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

    Mayu Ukai, Shiro Suzuki, Masato Yoshihara, Akira Yokoi, Nobuhisa Yoshikawa, Hiroaki Kajiyama, Fumitaka Kikkawa

    International Journal of Clinical Oncology   Vol. 27 ( 3 ) page: 609 - 618   2022.3

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

    DOI: 10.1007/s10147-021-02075-8

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    Other Link: https://link.springer.com/article/10.1007/s10147-021-02075-8/fulltext.html

  4. Clinical effects of cervical conization with positive margins in cervical cancer. International journal

    Yukari Nagao, Akira Yokoi, Kosuke Yoshida, Masanori Sumi, Masato Yoshihara, Satoshi Tamauchi, Yoshiki Ikeda, Nobuhisa Yoshikawa, Kimihiro Nishino, Kaoru Niimi, Hiroaki Kajiyama

    Scientific reports   Vol. 11 ( 1 ) page: 23288 - 23288   2021.12

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    Radical surgery after cervical conization is a common approach for the treatment of cervical cancer. In some cases, disease progression is observed after positive margins at conization, but the effect of conization on disease progression remains unclear. Thus, the aim of this study was to investigate the clinical outcomes of positive margins at conization in cervical cancer. A total of 101 patients who underwent cervical conization before radical hysterectomy and pelvic lymph node dissection were considered eligible by reviewing medical records. The association between the positive margins and patient outcomes, including subsequent lymph node metastasis, was evaluated. The rate of lymphovascular space invasion (LVSI) positivity at radical surgery was significantly higher in patients with positive margins (p = 0.017) than in those with negative margins, although there was no significant difference in the rate of pelvic lymph node metastasis (p = 0.155). Moreover, there was no significant difference in the overall survival or progression-free survival between the two groups (p = 0.332 and 0.200, respectively). A positive margin at conization presented no significant prognostic disadvantage; thus, diagnostic conization is one of the most suitable treatment options for early-stage cervical cancer that is difficult to accurately assess.

    DOI: 10.1038/s41598-021-02635-y

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  5. Extracellular microRNA profiling for prognostic prediction in patients with high‐grade serous ovarian carcinoma

    Kosuke Yoshida, Akira Yokoi, Juntaro Matsuzaki, Tomoyasu Kato, Takahiro Ochiya, Hiroaki Kajiyama, Yusuke Yamamoto

    Cancer Science   Vol. 112 ( 12 ) page: 4977 - 4986   2021.12

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/cas.15154

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15154

  6. Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology Reviewed International journal

    Akira Yokoi, Takahiro Ochiya

    Seminars in Cancer Biology   Vol. 74   page: 79 - 91   2021.9

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    Extracellular vesicles (EVs) such as exosomes are released by all living cells and contain diverse bioactive molecules, including nucleic acids, proteins, lipids, and metabolites. Accumulating evidence of EV-related functions has revealed that these tiny vesicles can mediate specific cell-to-cell communication. Within the tumor microenvironment, diverse cells are actively interacting with their surroundings via EVs facilitating tumor malignancy by regulating malignant cascades including angiogenesis, immune modulation, and metastasis. This review summarizes the recent studies of fundamental understandings of EVs from the aspect of EV heterogeneity and highlights the role of EVs in the various steps from oncogenic to metastatic processes. The recognition of EV subtypes is necessary to identify which pathways can be affected by EVs and which subtypes can be targeted in therapeutic approaches or liquid biopsies.

    DOI: 10.1016/j.semcancer.2021.03.032

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  7. Is cystectomy an option as conservative surgery for young patients with borderline ovarian tumor? A multi-institutional retrospective study. International journal

    Yoshiki Ikeda, Masato Yoshihara, Nobuhisa Yoshikawa, Satoshi Tamauchi, Akira Yokoi, Kimihiro Nishino, Kaoru Niimi, Hiroaki Kajiyama

    International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics     2021.8

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    OBJECTIVE: We investigated the impact of cystectomy for borderline ovarian tumor (BOT) on tumor recurrence in comparison with those receiving salpingo-oophorectomy using the inverse probability of treatment weighting (IPTW). METHODS: Between 1986 and 2017, 4,708 women with a malignant ovarian neoplasm were collected after a central pathological review and search of the medical records from 14 collaborating institutions. Among them, a total of 285 young women with stage I BOT were extracted. To compare recurrence-free survival (RFS) between the surgery groups, Cox regression analyses and IPTW-adjusted Kaplan-Meier method were employed. RESULTS: During a median follow-up of 62.0 (1.2-270.4) months, 10 patients (3.5%) developed recurrence. In multivariate analysis, the practice of cystectomy was not a significant prognostic indicator of RFS {hazard ratio (95% confidence interval): 1.276 (0.150-10.864), P=0.823}. In the IPTW-adjusted cohort, the 5-year RFS rates were 95.8 and 96.0% in patients receiving cystectomy and salpingo-oophorectomy, respectively (P=0.378). CONCLUSION: If patients are selected appropriately, cystectomy in itself may not increase tumor recurrence in young women with early-stage BOT. A large-scale prospective clinical study is necessary to validate this finding.

    DOI: 10.1002/ijgo.13844

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  8. CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance. International journal

    Shaolin Ma, Lingegowda S Mangala, Wen Hu, Emine Bayaktar, Akira Yokoi, Wei Hu, Sunila Pradeep, Sanghoon Lee, Paul D Piehowski, Alejandro Villar-Prados, Sherry Y Wu, Michael H McGuire, Olivia D Lara, Cristian Rodriguez-Aguayo, Christopher J LaFargue, Nicholas B Jennings, Karin D Rodland, Tao Liu, Vikas Kundra, Prahlad T Ram, Sundaram Ramakrishnan, Gabriel Lopez-Berestein, Robert L Coleman, Anil K Sood

    Cell reports   Vol. 36 ( 7 ) page: 109549 - 109549   2021.8

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    Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.

    DOI: 10.1016/j.celrep.2021.109549

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  9. Metabolome analysis reveals a diversity of cancer tissues in advanced epithelial ovarian cancer. International journal

    Kosuke Yoshida, Nobuhisa Yoshikawa, Kazuhisa Kitami, Satoshi Tamauchi, Yoshiki Ikeda, Akira Yokoi, Kimihiro Nishino, Kaoru Niimi, Hiroaki Kajiyama

    Cancer cell international   Vol. 21 ( 1 ) page: 314 - 314   2021.6

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    BACKGROUND: Epithelial ovarian cancer remains one of the leading causes of cancer deaths among women worldwide, and advanced epithelial ovarian cancer frequently metastasizes to the omentum. The characteristics of metastatic cancer may differ from those of primary ovarian cancer and reflect the unique omental microenvironment. This study investigated metabolomic differences in epithelial ovarian cancers. METHODS: Patients with advanced epithelial ovarian cancer were eligible for this study. Five patients underwent surgery and resection of paired primary ovarian and omental metastatic cancer at Nagoya University. Metabolome analysis was performed in these paired cancer and metastatic cancer tissues through a facility service (C-SCOPE) at Human Metabolome Technologies, Inc. The concentrations of 116 compounds were measured by CE-TOFMS and CE-QqQMS, and 30 metabolic parameters were calculated. For statistical analyses, Welch's t-test was used for comparisons between two independent groups. RESULTS: Metabolite profiles were all different, which reflects diversity among these cancer tissues. Of the measured compounds, urea was the only metabolite that was significantly decreased in omental metastatic cancers compared with the primary cancers (p = 0.031). Moreover, in omental metastatic cancers, the pentose phosphate pathway was more dominant than glycolysis. Furthermore, in some cases, lactic acids in omental metastatic cancers were markedly decreased compared with primary cancers. With regard to histological subtype, the total levels of amino acids, especially the percentage of glutamine, were significantly enriched in serous carcinomas compared with nonserous carcinomas (p = 0.004 and p = 0.001). Moreover, the reduced forms of glutathione and polyamines were also more abundant in serous carcinomas than in nonserous carcinomas (p = 0.025 and 0.048). CONCLUSIONS: The metabolite profiles differed depending on tumor location and histological subtype. Metabolome analysis may be a useful tool for identifying cancer diagnostic and prognostic markers.

    DOI: 10.1186/s12935-021-02014-7

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  10. Significance of Concurrent Chemoradiotherapy as Primary Treatment in Patients with Metastatic Cervical Cancer. Reviewed International journal

    Satomi Hattori, Nobuhisa Yoshikawa, Kazumasa Mogi, Kosuke Yoshida, Masato Yoshihara, Satoshi Tamauchi, Yoshiki Ikeda, Akira Yokoi, Kimihiro Nishino, Kaoru Niimi, Shiro Suzuki, Hiroaki Kajiyama

    Current oncology (Toronto, Ont.)   Vol. 28 ( 3 ) page: 1663 - 1672   2021.6

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    (1) This study investigated the prognostic impact of tumor size in patients with metastatic cervical cancer. (2) Methods: Seventy-three cervical cancer patients in our institute were stratified into two groups based on distant metastasis: para-aortic lymph node metastasis alone (IIIC2) or spread to distant visceral organs with or without para-aortic lymph node metastasis (IVB) to identify primary tumor size and concurrent chemoradiotherapy. (3) Results: The overall survival (OS) for patients with a tumor >6.9 cm in size was significantly poorer than that for patients with a tumor ≤6.9 cm in the IVB group (p = 0.0028); the corresponding five-year OS rates in patients with a tumor ≤6.9 and >6.9 cm were 53.3% and 13.4%, respectively. In the multivariate analysis, tumor size and primary treatment were significantly associated with survival in metastatic cervical cancer. (4) Conclusions: Tumor size ≤6.9 cm and concurrent chemoradiotherapy as the primary treatment were favorable prognostic factors for patients with metastatic cervical cancer.

    DOI: 10.3390/curroncol28030155

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  11. ChrXq27.3 miRNA cluster functions in cancer development. Reviewed International journal

    Kosuke Yoshida, Akira Yokoi, Yusuke Yamamoto, Hiroaki Kajiyama

    Journal of experimental & clinical cancer research : CR   Vol. 40 ( 1 ) page: 112 - 112   2021.3

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    MicroRNAs (miRNAs) regulate the expression of their target genes post-transcriptionally; thus, they are deeply involved in fundamental biological processes. miRNA clusters contain two or more miRNA-encoding genes, and these miRNAs are usually coexpressed due to common expression mechanisms. Therefore, miRNA clusters are effective modulators of biological pathways by the members coordinately regulating their multiple target genes, and an miRNA cluster located on the X chromosome q27.3 region has received much attention in cancer research recently. In this review, we discuss the novel findings of the chrXq27.3 miRNA cluster in various types of cancer.The chrXq27.3 miRNA cluster contains 30 mature miRNAs synthesized from 22 miRNA-encoding genes in an ~ 1.3-Mb region. The expressions of these miRNAs are usually negligible in many normal tissues, with the male reproductive system being an exception. In cancer tissues, each miRNA is dysregulated, compared with in adjacent normal tissues. The miRNA-encoding genes are not uniformly distributed in the region, and they are further divided into two groups (the miR-506-514 and miR-888-892 groups) according to their location on the genome. Most of the miRNAs in the former group are tumor-suppressive miRNAs that are further downregulated in various cancers compared with normal tissues. miR-506-3p in particular is the most well-known miRNA in this cluster, and it has various tumor-suppressive functions associated with the epithelial-mesenchymal transition, proliferation, and drug resistance. Moreover, other miRNAs, such as miR-508-3p and miR-509-3p, have similar tumor-suppressive effects. Hence, the expression of these miRNAs is clinically favorable as prognostic factors in various cancers. However, the functions of the latter group are less understood. In the latter group, miR-888-5p displays oncogenic functions, whereas miR-892b is tumor suppressive. Therefore, the functions of the miR-888-892 group are considered to be cell type- or tissue-specific.In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression, and the miRNAs themselves, their regulatory mechanisms, and their target genes might be promising therapeutic targets.

    DOI: 10.1186/s13046-021-01910-0

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  12. Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance. Reviewed International journal

    Kosuke Yoshida, Akira Yokoi, Mai Sugiyama, Shingo Oda, Kazuhisa Kitami, Satoshi Tamauchi, Yoshiki Ikeda, Nobuhisa Yoshikawa, Kimihiro Nishino, Kaoru Niimi, Shiro Suzuki, Fumitaka Kikkawa, Tsuyoshi Yokoi, Hiroaki Kajiyama

    Oncogene   Vol. 40 ( 7 ) page: 1255 - 1268   2021.2

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    Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.

    DOI: 10.1038/s41388-020-01595-3

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  13. Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype. Reviewed International journal

    Shaolin Ma, Michael H McGuire, Lingegowda S Mangala, Sanghoon Lee, Elaine Stur, Wen Hu, Emine Bayraktar, Alejandro Villar-Prados, Cristina Ivan, Sherry Y Wu, Akira Yokoi, Santosh K Dasari, Nicholas B Jennings, Jinsong Liu, Gabriel Lopez-Berestein, Prahlad Ram, Anil K Sood

    Cell reports   Vol. 34 ( 6 ) page: 108726 - 108726   2021.2

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    Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.

    DOI: 10.1016/j.celrep.2021.108726

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  14. A novel approach for liquid biopsy by using nuclear derived exosomes in ovarian cancer Reviewed International journal

    Yokoi Akira

    CANCER SCIENCE   Vol. 112   page: 986 - 986   2021.2

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  15. The role of chrXq27.3 miRNA cluster in advanced ovarian clear cell carcinoma Reviewed International journal

    Yoshida Kosuke, Yokoi Akira, Yoshihara Masato, Tamauchi Satoshi, Yoshikawa Nobuhisa, Nishino Kimihiro, Niimi Kaoru, Kikkawa Fumitaka, Kajiyama Hiroaki

    CANCER SCIENCE   Vol. 112   page: 291 - 291   2021.2

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  16. Luteolin suppresses Ovarian Cancer progression via decrease the expression of VRK1 Reviewed International journal

    Chang Xuboya, Kajiyama Hiroaki, Yoshikawa Nobuhisa, Yokoi Akira, Tamauchi Satoshi, Yoshihara Masato

    CANCER SCIENCE   Vol. 112   page: 770 - 770   2021.2

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  17. Intra-tumoral polarity induced by Notch signaling can be a novel therapeutic target for advanced ovarian cancer Reviewed International journal

    Yoshihara Masato, Sugiyama Mai, Koya Yoshihiro, Iyoshi Shohei, Kitami Kazuhisa, Uno Kaname, Mogi Kazumasa, Tano Sho, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE   Vol. 112   page: 363 - 363   2021.2

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  18. How do peritoneal mesothelial cells on adipose tissue attract ovarian cancer cells? Reviewed International journal

    Mogi Kazumasa, Yoshihara Masato, Kitami Kazuhisa, Iyoshi Shohei, Uno Kaname, Tano Sho, Sugiyama Mai, Koya Yoshihiro, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE   Vol. 112   page: 341 - 341   2021.2

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  19. Extracellular miRNAs as Predictive Biomarkers for Glypican-3-Derived Peptide Vaccine Therapy Response in Ovarian Clear Cell Carcinoma Reviewed International journal

    Mayu Ukai, Akira Yokoi, Kosuke Yoshida, Shiro Suzuki, Kiyosumi Shibata, Fumitaka Kikkawa, Tetsuya Nakatsura, Hiroaki Kajiyama

    Cancers   Vol. 13 ( 3 ) page: 550 - 550   2021.2

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    Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.

    DOI: 10.3390/cancers13030550

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  20. Exploring the biological roles of extracellular vesicles carrying nucleic acids in ovarian cancer Reviewed International journal

    Yokoi Akira

    CANCER SCIENCE   Vol. 112   page: 204 - 204   2021.2

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  21. Comprehensive analyses of small extracellular vesicles carrying nucleic acids in ovarian cancer Reviewed International journal

    Yokoi Akira, Ochiya Takahiro

    CANCER SCIENCE   Vol. 112   page: 973 - 973   2021.2

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  22. Active vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer Reviewed International journal

    Kitami Kazuhisa, Yoshihara Masato, Sugiyama Mai, Koya Yoshihiro, Iyoshi Shohei, Uno Kaname, Mogi Kazumasa, Tamauchi Satoshi, Yokoi Akira, Yoshikawa Nobuhisa, Nawa Akihiro, Kajiyama Hiroaki

    CANCER SCIENCE   Vol. 112   page: 351 - 351   2021.2

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  23. Establishment and characterization of cell lines from human endometrial epithelial and mesenchymal cells from patients with endometriosis Reviewed International journal

    Ayako Muraoka, Satoko Osuka, Tohru Kiyono, Miho Suzuki, Akira Yokoi, Tomohiko Murase, Kimihiro Nishino, Kaoru Niimi, Tomoko Nakamura, Maki Goto, Hiroaki Kajiyama, Yutaka Kondo, Fumitaka Kikkawa

    F&S Science   Vol. 1 ( 2 ) page: 195 - 205   2020.11

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    DOI: 10.1016/j.xfss.2020.09.001

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  24. The clinical impact of intra- and extracellular miRNAs in ovarian cancer. Reviewed International journal

    Kosuke Yoshida, Akira Yokoi, Tomoyasu Kato, Takahiro Ochiya, Yusuke Yamamoto

    Cancer science   Vol. 111 ( 10 ) page: 3435 - 3444   2020.10

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    Ovarian cancer is the most lethal gynecological cancer due to lack of early screening methods and acquired drug resistance. MicroRNAs (miRNAs) are effective post-transcriptional regulators that are transferred by extracellular vesicles, such as exosomes. Numerous studies have revealed that miRNAs are differentially expressed in epithelial ovarian cancer and act either as oncogenes or tumor suppressor genes. Cancer cells secrete exosomes containing miRNAs, which exert various effects on the components of the tumor microenvironment, including cancer-associated fibroblasts, macrophages, and adipocytes. Conversely, cancer cells also receive exosomes from these cells. As a result of cell-to-cell communication, epithelial ovarian cancer acquires a more aggressive phenotype and resistance to multiple drugs. In addition, some circulating miRNAs are protected from RNase degradation in the peripheral blood and can be potential non-invasive biomarkers. In particular, the combination of several circulating miRNAs enhances the accuracy of cancer screening. Likewise, comprehensive analyses revealed specific miRNA signatures in non-epithelial ovarian tumors and several miRNAs contributing to alterations of carcinogenic pathways. Overall, miRNAs play a crucial role in ovarian cancer progression. In this review, we discuss the emerging roles of intra- and extracellular miRNAs in ovarian cancers. In the near future, miRNAs will be practical biomarkers and computational deep learning will help in the clinical application of miRNAs. Moreover, miRNAs are potential therapeutic targets and agents, and there are ongoing clinical trials of miRNA replacement therapy. Therefore, accelerating research on miRNA might improve the prognosis of patients with ovarian cancer.

    DOI: 10.1111/cas.14599

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  25. Ovarian cancer-associated mesothelial cells induce acquired platinum-resistance in peritoneal metastasis via the FN1/Akt signaling pathway. Reviewed International journal

    Masato Yoshihara, Hiroaki Kajiyama, Akira Yokoi, Mai Sugiyama, Yoshihiro Koya, Yoshihiko Yamakita, Wenting Liu, Kae Nakamura, Yoshinori Moriyama, Hiroaki Yasui, Shiro Suzuki, Yusuke Yamamoto, Carmela Ricciardelli, Akihiro Nawa, Kiyosumi Shibata, Fumitaka Kikkawa

    International journal of cancer   Vol. 146 ( 8 ) page: 2268 - 2280   2020.4

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    Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

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  26. Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis. Reviewed International journal

    Masato Yoshihara, Hiroaki Kajiyama, Satoshi Tamauchi, Shohei Iyoshi, Akira Yokoi, Shiro Suzuki, Michiyasu Kawai, Tetsuro Nagasaka, Kunihiko Takahashi, Shigeyuki Matsui, Fumitaka Kikkawa

    Japanese journal of clinical oncology   Vol. 50 ( 2 ) page: 145 - 151   2020.2

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    BACKGROUND: The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. METHODS: We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. RESULTS: Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P = 0.696) and recurrence-free survival (P = 0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. CONCLUSIONS: The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

    DOI: 10.1093/jjco/hyz163

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  27. Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma. Reviewed International journal

    Akira Yokoi, Juntaro Matsuzaki, Yusuke Yamamoto, Keisei Tate, Yutaka Yoneoka, Hanako Shimizu, Takashi Uehara, Mitsuya Ishikawa, Satoko Takizawa, Yoshiaki Aoki, Ken Kato, Tomoyasu Kato, Takahiro Ochiya

    Cancer science   Vol. 110 ( 12 ) page: 3718 - 3726   2019.12

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    Uterine leiomyosarcoma (ULMS) is the major subtype of uterine sarcoma (US) and contributes to uterine cancer deaths. Although preoperative diagnosis of US remains challenging, frequent application of laparoscopic surgery for benign uterine leiomyomas (ULM) requires precise exclusion of US. MicroRNAs are stably present in the bloodstream, and the application of circulating miRNAs as disease biomarkers has been recognized. In the present study, we aimed to identify diagnostic biomarkers for distinguishing US from ULM by focusing on circulating miRNAs. All serum samples were collected preoperatively between 2009 and 2017, and all cases were histopathologically diagnosed. Whole miRNA profiles were obtained using a miRNA microarray. By analyzing expression levels of the miRNAs, candidate miRNAs were selected based on diagnostic performance in discriminating US from ULM, and a diagnostic model was then constructed. A total of 90 serum samples were analyzed, and clustering analyses revealed that the profiles of ULMS were distinct from those of controls. Based on leave-one-out cross-validation, seven miRNAs were selected as biomarker candidates. Based on model construction, the optimal model consisted of two miRNAs (miR-1246 and miR-191-5p), with an area under the receiver operating characteristic curve (AUC) for identifying ULMS of 0.97 (95% confidence interval [CI], 0.91-1.00). In contrast, serum lactate dehydrogenase had an AUC of only 0.64 (95% CI, 0.34-0.94). Seven serum miRNAs with high diagnostic performance for preoperative US screening were detected, and a promising diagnostic model for ULMS was generated.

    DOI: 10.1111/cas.14215

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  28. Unique miRNA profiling of squamous cell carcinoma arising from ovarian mature teratoma: comprehensive miRNA sequence analysis of its molecular background. Reviewed International journal

    Kosuke Yoshida, Akira Yokoi, Takumi Kagawa, Shingo Oda, Satomi Hattori, Satoshi Tamauchi, Yoshiki Ikeda, Nobuhisa Yoshikawa, Kimihiro Nishino, Fumi Utsumi, Kaoru Niimi, Shiro Suzuki, Kiyosumi Shibata, Hiroaki Kajiyama, Tsuyoshi Yokoi, Fumitaka Kikkawa

    Carcinogenesis   Vol. 40 ( 12 ) page: 1435 - 1444   2019.12

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    Owing to its rarity, the carcinogenesis and molecular biological characteristics of squamous cell carcinoma arising from mature teratoma remain unclear. This study aims to elucidate the molecular background of malignant transformation from the aspects of microRNA (miRNA) profiling. We examined 7 patients with squamous cell carcinoma and 20 patients with mature teratoma and extracted their total RNA from formalin-fixed paraffin-embedded tissues. Then we prepared small RNA libraries and performed comprehensive miRNA sequencing. Heatmap and principal component analysis revealed markedly different miRNA profiling in cancer, normal ovarian and mature teratoma tissues. Then we narrowed down cancer-related miRNAs, comparing paired-cancer and normal ovaries. Comparisons of cancer and mature teratoma identified two markedly upregulated miRNAs (miR-151a-3p and miR-378a-3p) and two markedly downregulated miRNAs (miR-26a-5p and miR-99a-5p). In addition, these findings were validated in fresh cancer tissues of patient-derived xenograft (PDX) models. Moreover, several miRNAs, including miR-151a-3p and miR-378a-3p, were elevated in the murine plasma when tumor tissues were enlarged although miR-26a-5p and miR-99a-5p were not elucidated in the murine plasma. Finally, we performed target prediction and functional annotation analysis in silico and indicated that targets genes of these miRNAs markedly correlated with cancer-related pathways, including 'pathway in cancer' and 'cell cycle'. In conclusion, this is the first study on miRNA sequencing for squamous cell carcinoma arising from mature teratoma. The study identified four cancer-related miRNAs that were considered to be related to the feature of malignant transformation. Moreover, miRNAs circulating in the murine plasma of the PDX model could be novel diagnostic biomarkers.

    DOI: 10.1093/carcin/bgz135

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  29. COMPREHENSIVE MIRNA SEQUENCING OF SQUAMOUS CELL CARCINOMA ARISING FROM OVARIAN MATURE TERATOMA Reviewed International journal

    Yoshida K., Yokoi A., Tamauchi S., Ikeda Y., Yoshikawa N., Nishino K., Niimi K., Suzuki S., Kajiyama H., Kikkawa F.

    INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER   Vol. 29   page: A544 - A545   2019.11

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    DOI: 10.1136/ijgc-2019-ESGO.1079

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  30. Mechanisms of nuclear content loading to exosomes Reviewed International journal

    Akira Yokoi, Alejandro Villar-Prados, Paul Allen Oliphint, Jianhua Zhang, Xingzhi Song, Peter De Hoff, Robert Morey, Jinsong Liu, Jason Roszik, Karen Clise-Dwyer, Jared K. Burks, Theresa J. O’Halloran, Louise C. Laurent, Anil K. Sood

    Science Advances   Vol. 5 ( 11 ) page: eaax8849   2019.11

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    Exosome cargoes are highly varied and include proteins, small RNAs, and genomic DNA (gDNA). The presence of gDNA suggests that different intracellular compartments contribute to exosome loading, resulting in distinct exosome subpopulations. However, the loading of gDNA and other nuclear contents into exosomes (nExo) remains poorly understood. Here, we identify the relationship between cancer cell micronuclei (MN), which are markers of genomic instability, and nExo formation. Imaging flow cytometry analyses reveal that 10% of exosomes derived from cancer cells and <1% of exosomes derived from blood and ascites from patients with ovarian cancer carry nuclear contents. Treatment with genotoxic drugs resulted in increased MN and nExos both in vitro and in vivo. We observed that multivesicular body precursors and exosomal markers, such as the tetraspanins, directly interact with MN. Collectively, this work provides new insights related to nExos, which have implications for cancer biomarker development.

    DOI: 10.1126/sciadv.aax8849

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  31. Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts. Reviewed International journal

    Yutaka Naito, Yusuke Yamamoto, Naoya Sakamoto, Iwao Shimomura, Akiko Kogure, Minami Kumazaki, Akira Yokoi, Masakazu Yashiro, Tohru Kiyono, Kazuyoshi Yanagihara, Ryou-U Takahashi, Kosei Hirakawa, Wataru Yasui, Takahiro Ochiya

    Oncogene   Vol. 38 ( 28 ) page: 5566 - 5579   2019.7

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    Cancer-associated fibroblasts (CAFs), one of the major components of a tumour microenvironment, comprise heterogeneous populations involved in tumour progression. However, it remains obscure how CAF heterogeneity is governed by cancer cells. Here, we show that cancer extracellular vesicles (EVs) induce a series of chemokines in activated fibroblasts and contribute to the formation of the heterogeneity. In a xenograft model of diffuse-type gastric cancer, we showed two distinct fibroblast subpopulations with alpha-smooth muscle actin (α-SMA) expression or chemokine expression. MicroRNAs (miRNAs) profiling of the EVs and the transfection experiment suggested that several miRNAs played a role in the induction of chemokines such as CXCL1 and CXCL8 in fibroblasts, but not for the myofibroblastic differentiation. Clinically, aberrant activation of CXCL1 and CXCL8 in CAFs correlated with poorer survival in gastric cancer patients. Thus, this link between chemokine expression in CAFs and tumour progression may provide novel targets for anticancer therapy.

    DOI: 10.1038/s41388-019-0832-4

    PubMed

  32. A landmark in drug discovery based on complex natural product synthesis.

    Kawano S, Ito K, Yahata K, Kira K, Abe T, Akagi T, Asano M, Iso K, Sato Y, Matsuura F, Ohashi I, Matsumoto Y, Isomura M, Sasaki T, Fukuyama T, Miyashita Y, Kaburagi Y, Yokoi A, Asano O, Owa T, Kishi Y

    Scientific reports   Vol. 9 ( 1 ) page: 8656   2019.6

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    DOI: 10.1038/s41598-019-45001-9

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  33. Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer. Reviewed International journal

    Iwao Shimomura, Akira Yokoi, Isaku Kohama, Minami Kumazaki, Yuji Tada, Koichiro Tatsumi, Takahiro Ochiya, Yusuke Yamamoto

    Cancer letters   Vol. 451   page: 11 - 22   2019.6

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    KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancer (NSCLC). Mutations in KRAS are detected in 30% of NSCLC cases, with most of them occurring in codons 12 and 13 and less commonly in others. Despite intense efforts to develop drugs targeting mutant KRAS, no effective therapeutic strategies have been successfully tested in clinical trials. Here, we investigated molecular targets for KRAS-activated lung cancer cells using a drug library. A total of 1271 small molecules were screened in KRAS-mutant and wild-type lung cancer cell lines. The screening identified the cytotoxic effects of benzimidazole derivatives on KRAS-mutant lung cancer cells. Treatments with two benzimidazole derivatives, methiazole and fenbendazole-both of which are structurally specific-yielded significant suppression of the RAS-related signaling pathways in KRAS-mutated cells. Moreover, combinatorial therapy with methiazole and trametinib, a MEK inhibitor, induced synergistic effects in KRAS-mutant lung cancer cells. Our study demonstrates that these benzimidazole derivatives play an important role in suppressing KRAS-mutant lung cancer cells, thus offering a novel combinatorial therapeutic approach against such cancer cells.

    DOI: 10.1016/j.canlet.2019.03.002

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  34. PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination. Reviewed International journal

    Yang Peng, Hiroaki Kajiyama, Hong Yuan, Kae Nakamura, Masato Yoshihara, Akira Yokoi, Kayo Fujikake, Hiroaki Yasui, Nobuhisa Yoshikawa, Shiro Suzuki, Takeshi Senga, Kiyosumi Shibata, Fumitaka Kikkawa

    Cancer letters   Vol. 442   page: 181 - 192   2019.2

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    The mesothelium, covered by a continuous monolayer of mesothelial cells, is the first protective barrier against metastatic ovarian cancer. However, mesothelial cells release tumor-promoting factors that accelerate the process of peritoneal metastasis. We identified cancer-associated mesothelial cells (CAMs) that had tumor-promoting potential. Here, we found that plasminogen activator inhibitor-1 (PAI-1) induced the formation of CAMs, after which CAMs increasingly secreted the oncogenic factors interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5), further promoting the metastasis of ovarian cancer cells in a feedback loop. After the formation of CAMs, PAI-1 activated the nuclear factor kappa B (NFκB) pathway in the CAMs, thus transcriptionally upregulating the expression of the downstream NFκB targets IL-8 and CXCL5. Moreover, PAI-1 correlated with peritoneal metastasis in ovarian cancer patients and indicated a poor prognosis. In both ex vivo and in vivo models, after PAI-1 expression was knocked down, the metastasis of ovarian cancer cells decreased significantly. Therefore, targeting PAI-1 may provide a potential target for future therapeutics to prevent the formation of CAMs and alleviate peritoneal metastasis in ovarian cancer patients.

    DOI: 10.1016/j.canlet.2018.10.027

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  35. Investigation of postpartum hemorrhage related to assisted reproductive technology (ART) pregnancy managed by in-hospital midwife care system

    OSHIMA Kazumi, YOKOI Akira, SHIBATA Sachiko, MANO Makiko

    Journal of Japan Academy of Midwifery   Vol. 32 ( 2 ) page: 169 - 177   2018.12

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    <p><b>Purpose</b></p><p>The authors' birth center is an in-hospital midwifery facility annexed to the Perinatal Medical Center. Even if the course of pregnancy and delivery is uneventful, unexpected massive bleeding can occur after childbirth. Pregnancies conceived via assisted reproductive technology (ART) are said to be a risk factor for <i>placenta accreta</i>; and <i>placenta accreta</i> can cause critical obstetrical hemorrhage. In our facility, if a parturient conceived via ART wishes to give birth in an in-hospital midwifery unit, childbirth is carried out in a birth center with the permission of the obstetrician. We conducted a case-control study about postpartum hemorrhage (PPH) to examine the safety of giving birth of pregnant women conceived via ART (fresh embryo transfer and cryopreserved embryo transfer) in an in-hospital midwifery care.</p><p><b>Subjects and Methods</b></p><p>During the survey period between April 2013 and March 2016, the total number of birth center deliveries was 604, including 567 not conceived through ART and 37 conceived through ART: fresh embryo transfer in 9 cases and cryopreserved embryo transfer (CET) in 28 cases. We carried out a statistical analysis of the amount of postpartum bleeding, the amount of bleeding during the 24 hours following delivery, and the frequency of PPH (postpartum bleeding of 500mL or more, or bleeding of 800mL or more during the 24 hours following delivery) among pregnancies not conceived through ART, pregnancies conceived through fresh embryo transfer, and pregnancies conceived through CET. Multiple linear regression analysis of the amount of postpartum bleeding and the amount of bleeding during the 24 hours following delivery was performed, and the frequency of PPH was determined using multivariate logistic analysis.</p><p><b>Results</b></p><p>The amount of postpartum bleeding and the amount during the 24 hours following delivery were significantly greater among pregnancies conceived through CET than among those not conceived through ART; the frequency of PPH was also significantly higher among pregnancies conceived through CET than among those not conceived through ART. In addition, PPH consisted of critical obstetrical hemorrhage in 4 cases, 3 of which occurred in mothers pregnant with fetuses conceived through ART using CET.</p><p><b>Conclusions</b></p><p>Our study suggested that pregnancy conceived through CET was a risk factor for PPH. Regarding care system and eligibility for giving birth of pregnant women conceived through CET in an in-hospital midwifery unit, further investigations are needed.</p>

    DOI: 10.3418/jjam.jjam-2017-0048

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  36. Cancer-associated mesothelial cells as a potential therapeutic target in epithelial ovarian cancer Reviewed International journal

    Yoshihara Masato, Kajiyama Hiroaki, Sugiyama Mai, Koya Yoshihiro, Ryu Buntei, Yokoi Akira, Yamamoto Yusuke, Kikkawa Fumitaka

    CANCER SCIENCE   Vol. 109   page: 247 - 247   2018.12

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  37. The role of extracellular RNAs in ovarian cancer Reviewed International journal

    Yokoi Akira, Yoshioka Yusuke, Yamamoto Yusuke, Matsuzaki Juntaro, Kato Tomoyasu, Kato Ken, Kajiyama Hiroaki, Kikkawa Fumitaka, Ochiya Takahiro

    CANCER SCIENCE   Vol. 109   page: 351 - 351   2018.12

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  38. Notch signaling enhances the mutual association with epithelial ovarian cancer and mesothelial cells Reviewed International journal

    Sugiyama Mai, Yoshihara Masato, Koya Yoshihiro, Yokoi Akira, Ryu Buntei, Kikkawa Fumitaka, Kajiyama Hiroaki

    CANCER SCIENCE   Vol. 109   page: 864 - 864   2018.12

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  39. Integrated extracellular microRNA profiling for ovarian cancer screening. Reviewed International journal

    Akira Yokoi, Juntaro Matsuzaki, Yusuke Yamamoto, Yutaka Yoneoka, Kenta Takahashi, Hanako Shimizu, Takashi Uehara, Mitsuya Ishikawa, Shun-Ichi Ikeda, Takumi Sonoda, Junpei Kawauchi, Satoko Takizawa, Yoshiaki Aoki, Shumpei Niida, Hiromi Sakamoto, Ken Kato, Tomoyasu Kato, Takahiro Ochiya

    Nature communications   Vol. 9 ( 1 ) page: 4319 - 4319   2018.10

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    A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9-10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.

    DOI: 10.1038/s41467-018-06434-4

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  40. Carcinoma-associated mesothelial cells promote dissemination and platinum resistance in epithelial ovarian cancer. Reviewed International journal

    Yoshihara Masato, Kajiyama Hiroaki, Sugiyama Mai, Yasui Hiroaki, Koya Yoshihiro, Yamakita Yoshihiko, Ryu Buntei, Yokoi Akira, Yamamoto Yusuke, Kikkawa Fumitaka

    CANCER SCIENCE   Vol. 109   page: 118 - 118   2018.1

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  41. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer Reviewed International journal

    Yokoi Akira, Yoshioka Yusuke, Yamamoto Yusuke, Ishikawa Mitsuya, Kato Tomoyasu, Kiyono Tohru, Kajiyama Hiroaki, Kikkawa Fumitaka, Ochiya Takahiro

    CANCER SCIENCE   Vol. 109   page: 29 - 29   2018.1

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  42. 既存薬ライブラリーを用いた、活性型Ras変異がんを標的とする分子標的治療の探索 Reviewed International journal

    下村 巌, 横井 暁, 山本 雄介, 多田 裕司, 巽 浩一郎, 落谷 孝広

    生命科学系学会合同年次大会   Vol. 2017年度   page: [3P - 0974]   2017.12

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  43. A combination of circulating miRNAs for the early detection of ovarian cancer. Reviewed International journal

    Akira Yokoi, Yusuke Yoshioka, Akihiro Hirakawa, Yusuke Yamamoto, Mitsuya Ishikawa, Shun-Ichi Ikeda, Tomoyasu Kato, Kaoru Niimi, Hiroaki Kajiyama, Fumitaka Kikkawa, Takahiro Ochiya

    Oncotarget   Vol. 8 ( 52 ) page: 89811 - 89823   2017.10

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    Ovarian cancer is the leading cause of gynecologic cancer mortality, due to the difficulty of early detection. Current screening methods lack sufficient accuracy, and it is still challenging to propose a new early detection method that improves patient outcomes with less-invasiveness. Although many studies have suggested the utility of circulating microRNAs in cancer detection, their potential for early detection remains elusive. Here, we develop novel predictive models using a combination of 8 circulating serum miRNAs. This method was able to successfully distinguish ovarian cancer patients from healthy controls (area under the curve, 0.97; sensitivity, 0.92; and specificity, 0.91) and early-stage ovarian cancer from patients with benign tumors (0.91, 0.86 and 0.83, respectively). This method also enables subtype classification in 4 types of epithelial ovarian cancer. Furthermore, it is found that most of the 8 miRNAs were packaged in extracellular vesicles, including exosomes, derived from ovarian cancer cells, and they were circulating in murine blood stream. The circulating miRNAs described in this study may serve as biomarkers for ovarian cancer patients. Early detection and subtype determination prior to surgery are crucial for clinicians to design an effective treatment strategy for each patient, as is the goal of precision medicine.

    DOI: 10.18632/oncotarget.20688

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  44. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Reviewed International journal

    Akira Yokoi, Yusuke Yoshioka, Yusuke Yamamoto, Mitsuya Ishikawa, Shun-Ichi Ikeda, Tomoyasu Kato, Tohru Kiyono, Fumitaka Takeshita, Hiroaki Kajiyama, Fumitaka Kikkawa, Takahiro Ochiya

    Nature communications   Vol. 8   page: 14470 - 14470   2017.3

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    Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

    DOI: 10.1038/ncomms14470

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  45. Diagnostic potential of multiple miRNAs for detecting early ovarian cancer

    Yokoi Akira, Yoshioka Yusuke, Kato Tomoyasu, Kajiyama Hiroaki, Kikkawa Fumitaka, Ochiya Takahiro

    Japan Journal of Molecular Tumor Marker Research   Vol. 32 ( 0 ) page: 27   2017

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    DOI: 10.11241/jsmtmr.32.27

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MISC 38

  1. 血液マイクロRNAによる子宮肉腫と変性筋腫の術前鑑別診断

    加藤 友康, 横井 暁, 松崎 潤太郎, 山本 雄介, 舘 慶生, 米岡 完, 清水 華子, 植原 貴史, 石川 光也, 滝澤 聡子, 青木 良晃, 加藤 健, 落谷 孝広, 東レ株式会社新事業開発部門DNAチップG

    日本婦人科腫瘍学会雑誌   Vol. 39 ( 1 ) page: 297 - 297   2021.1

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  2. 当院での早期子宮体癌に対する腹腔鏡下子宮悪性腫瘍手術の後方視的検討

    茂木 一将, 池田 芳紀, 秋田 寛佳, 伊吉 祥平, 宇野 枢, 小田 結加里, 甲木 聡, 服部 諭美, 大野 真由, 北見 和久, 村上 真由子, 渡邉 絵里, 玉内 学志, 横井 暁, 芳川 修久, 西野 公博, 新美 薫, 中村 智子, 大須賀 智子, 梶山 広明

    日本産科婦人科内視鏡学会雑誌   Vol. 36 ( Suppl.I ) page: [O - 465]   2020.11

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  3. 核由来DNA搭載エクソソームを用いた新規リキッドバイオプシー戦略 International journal

    横井 暁

    日本癌学会総会記事   Vol. 79回   page: IS5 - 6   2020.10

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  4. 卵巣がんにおける核酸搭載細胞外小胞の包括的解析 International journal

    横井 暁, 落谷 孝広

    日本癌学会総会記事   Vol. 79回   page: ISEV - 5   2020.10

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  5. LuteolinはVRK1の発現を低下させることにより卵巣癌の進行抑制 International journal

    常 続博雅, 梶山 広明, 芳川 修久, 横井 暁, 玉内 学志, 吉原 雅人

    日本癌学会総会記事   Vol. 79回   page: PE14 - 3   2020.10

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  6. I期卵巣癌における術中被膜破綻と縮小手術及び術後化学療法の予後に与える影響 International journal

    吉原 雅人, 宇野 枢, 北見 和久, 伊吉 祥平, 田野 翔, 茂木 一将, 玉内 学志, 横井 暁, 池田 芳紀, 芳川 修久, 梶山 広明

    日本癌治療学会学術集会抄録集   Vol. 58回   page: O18 - 6   2020.10

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  7. 活性型ビタミンDは腹膜の中皮間葉転換を阻害し、卵巣癌腹膜播種を抑制する International journal

    北見 和久, 吉原 雅人, 杉山 麻衣, 小屋 美博, 伊吉 祥平, 宇野 枢, 茂木 一将, 玉内 学志, 横井 暁, 芳川 修久, 那波 明宏, 梶山 広明

    日本癌学会総会記事   Vol. 79回   page: OE10 - 1   2020.10

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  8. 卵巣がんにおける核酸搭載細胞外小胞の機能解析と臨床応用 International journal

    横井 暁

    日本癌学会総会記事   Vol. 79回   page: YIA - 2   2020.10

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  9. 進行卵巣癌におけるNotchシグナルを介した腫瘍内細胞極性の解明と標的化 International journal

    吉原 雅人, 杉山 麻衣, 小屋 美博, 伊吉 祥平, 北見 和久, 宇野 枢, 茂木 一将, 田野 翔, 玉内 学志, 横井 暁, 芳川 修久, 那波 明宏, 梶山 広明

    日本癌学会総会記事   Vol. 79回   page: OE11 - 2   2020.10

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  10. 卵巣癌の腹膜播種における腹膜中皮と脂肪組織の影響 International journal

    茂木 一将, 吉原 雅人, 北見 和久, 伊吉 祥平, 宇野 枢, 田野 翔, 杉山 麻衣, 小屋 美博, 玉内 学志, 横井 暁, 芳川 修久, 那波 明宏, 梶山 広明

    日本癌学会総会記事   Vol. 79回   page: OE10 - 2   2020.10

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  11. 卵巣明細胞癌におけるchrXq27.3 miRNAクラスターの転移・再発への役割 International journal

    吉田 康将, 横井 暁, 吉原 雅人, 玉内 学志, 芳川 修久, 西野 公博, 新美 薫, 吉川 史隆, 梶山 広明

    日本癌学会総会記事   Vol. 79回   page: OE5 - 2   2020.10

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  12. 卵巣性索間質性腫瘍I期における妊孕性温存手術の後方視的解析 International journal

    茂木 一将, 吉原 雅人, 伊吉 祥平, 宇野 枢, 北見 和久, 玉内 学志, 横井 暁, 芳川 修久, 池田 芳紀, 河井 通泰, 長坂 徹郎, 梶山 広明

    日本癌治療学会学術集会抄録集   Vol. 58回   page: O64 - 3   2020.10

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  13. I期卵巣癌における術中被膜破綻と縮小手術及び術後化学療法の予後に与える影響

    吉原 雅人, 宇野 枢, 北見 和久, 伊吉 祥平, 田野 翔, 茂木 一将, 玉内 学志, 横井 暁, 池田 芳紀, 芳川 修久, 梶山 広明

    日本癌治療学会学術集会抄録集   Vol. 58回   page: O18 - 6   2020.10

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  14. 卵巣性索間質性腫瘍I期における妊孕性温存手術の後方視的解析

    茂木 一将, 吉原 雅人, 伊吉 祥平, 宇野 枢, 北見 和久, 玉内 学志, 横井 暁, 芳川 修久, 池田 芳紀, 河井 通泰, 長坂 徹郎, 梶山 広明

    日本癌治療学会学術集会抄録集   Vol. 58回   page: O64 - 3   2020.10

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  15. 隣接細胞間コミュニケーションによる卵巣癌腹膜播種微小環境の形成 International journal

    杉山 麻衣, 梶山 広明, 吉原 雅人, 小屋 美博, 横井 暁, 山下 守, 那波 明宏, 吉川 史隆

    日本産科婦人科学会雑誌   Vol. 72 ( 臨増 ) page: S - 401   2020.3

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  16. 【産婦人科領域で話題の新技術-時代の潮流に乗り遅れないための羅針盤】(Part2)注目の最新技術 腫瘍 マイクロRNA測定技術を用いた卵巣がんの早期診断 International journal

    横井 暁, 落谷 孝広

    臨床婦人科産科   Vol. 73 ( 12 ) page: 1222 - 1226   2019.12

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    <文献概要>●血液中を循環するマイクロRNAをバイオマーカーとして臨床応用することを目的とした取り組み.●卵巣がん患者群において有意に変化する複数のマイクロRNAを同定し,それらの組み合わせにより,早期から高精度でがんの存在を検出できる診断モデルを作成.●卵巣がん診断血液スクリーニングの実現に大きな前進をもたらす成果である.

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01564&link_issn=&doc_id=20191202060012&doc_link_id=10.11477%2Fmf.1409209874&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1409209874&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

  17. 婦人科がんの発生・病態・治療に関する最新の知見 癌関連中皮細胞の卵巣癌腹膜播種進展における役割(Recent advances in generation, biology, and treatment of gynecologic cancer Carcinoma-associated mesothelial cells as a novel therapeutic target in epithelial ovarian cancer) International journal

    吉原 雅人, 梶山 広明, 杉山 麻衣, 小屋 美博, 横井 暁, 伊吉 祥平, 吉川 史隆

    日本癌学会総会記事   Vol. 78回   page: SST7 - 4   2019.9

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  18. エクソソーム分泌を阻害する低分子化合物のスクリーニング(Discovery of an inhibitor for EV secretion in cancer cells using a small-molecule library approach) International journal

    吉岡 祐亮, 横井 暁, 落谷 孝広

    日本癌学会総会記事   Vol. 78回   page: E - 3047   2019.9

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  19. エクソソーム分泌を阻害する低分子化合物のスクリーニング(Discovery of an inhibitor for EV secretion in cancer cells using a small-molecule library approach) International journal

    吉岡 祐亮, 横井 暁, 落谷 孝広

    日本癌学会総会記事   Vol. 78回   page: E - 3047   2019.9

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  20. がん研究における女性研究者(第6回) 腹膜中皮細胞はNotchシグナルを介して卵巣がん細胞の増殖を亢進する(Women scientists in cancer research Mesothelial cells promote ovarian cancer proliferation through Notch signaling pathway) International journal

    杉山 麻衣, 梶山 広明, 吉原 雅人, 小屋 美博, 横井 暁, 那波 明宏, 吉川 史隆

    日本癌学会総会記事   Vol. 78回   page: SS - 1   2019.9

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  21. がん研究における女性研究者(第6回) 腹膜中皮細胞はNotchシグナルを介して卵巣がん細胞の増殖を亢進する(Women scientists in cancer research Mesothelial cells promote ovarian cancer proliferation through Notch signaling pathway) International journal

    杉山 麻衣, 梶山 広明, 吉原 雅人, 小屋 美博, 横井 暁, 那波 明宏, 吉川 史隆

    日本癌学会総会記事   Vol. 78回   page: SS - 1   2019.9

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  22. 婦人科がんの発生・病態・治療に関する最新の知見 癌関連中皮細胞の卵巣癌腹膜播種進展における役割(Recent advances in generation, biology, and treatment of gynecologic cancer Carcinoma-associated mesothelial cells as a novel therapeutic target in epithelial ovarian cancer) International journal

    吉原 雅人, 梶山 広明, 杉山 麻衣, 小屋 美博, 横井 暁, 伊吉 祥平, 吉川 史隆

    日本癌学会総会記事   Vol. 78回   page: SST7 - 4   2019.9

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  23. 卵巣成熟奇形腫の悪性転化における特徴的なmiRNA発現プロファイルの同定(Identification of unique miRNA profiling in squamous cell carcinoma arising from mature teratoma of ovary) International journal

    吉田 康将, 横井 暁, 玉内 学志, 吉原 雅人, 芳川 修久, 西野 公博, 新美 薫, 鈴木 史朗, 梶山 広明, 吉川 史隆

    日本癌学会総会記事   Vol. 78回   page: P - 1350   2019.9

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  24. 卵巣成熟奇形腫の悪性転化における特徴的なmiRNA発現プロファイルの同定(Identification of unique miRNA profiling in squamous cell carcinoma arising from mature teratoma of ovary) International journal

    吉田 康将, 横井 暁, 玉内 学志, 吉原 雅人, 芳川 修久, 西野 公博, 新美 薫, 鈴木 史朗, 梶山 広明, 吉川 史隆

    日本癌学会総会記事   Vol. 78回   page: P - 1350   2019.9

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  25. 卵巣がん腹膜播種形成時における腹膜の変化と役割 International journal

    杉山 麻衣, 梶山 広明, 吉原 雅人, 小屋 美博, 横井 暁, 山下 守, 那波 明宏, 吉川 史隆

    日本産科婦人科学会雑誌   Vol. 71 ( 臨増 ) page: S - 293   2019.2

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  26. 院内助産で分娩管理を行った生殖補助医療(ART)妊婦の産後過多出血の検討 International journal

    大島 和美, 横井 暁, 柴田 幸子, 真野 真紀子

    日本助産学会誌   Vol. 32 ( 2 ) page: 169 - 177   2018.12

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    目的 バースセンター(以下BC)は、総合周産期母子医療センターに併設する院内助産施設である。BCでは妊娠分娩経過は正常であっても、出産後に予期せぬ多量出血を経験することがある。生殖補助医療(以下ART)妊娠は癒着胎盤のリスク因子と言われており、且つ癒着胎盤は産科危機的出血の原因となり得る。当施設ではART妊娠であっても院内助産分娩希望があれば、産科医許可のもとBCで分娩を取扱っている。本研究ではART妊娠(新鮮胚移植妊娠、融解胚移植妊娠)の産後過多出血(以下PPH)を検証し、院内助産におけるリスク評価、及び対応を検討した。対象と方法 研究デザインは症例対照研究である。対象は2013年4月から2016年3月の調査期間中にBCで取り扱った分娩604例で、うち非ART妊娠は567例、ART妊娠は37例(新鮮胚移植9例、融解胚移植28例)であった。非ART妊娠と新鮮胚移植妊娠、融解胚移植妊娠で分娩後出血量、産褥24時間出血量、及びPPH(分娩後出血500ml以上、産褥24時間出血800ml以上)頻度の統計解析を行った。分娩後出血量、産褥24時間出血量を重回帰分析で、PPH頻度を多変量ロジスティック分析により検証した。結果 融解胚移植妊娠は分娩後出血量、産褥24時間出血量が非ART妊娠より有意に多く、PPHの頻度は非ART妊娠より有意に高かった。PPHのうち4例が産科危機的出血であったが、うち3例は融解胚移植のART妊婦であった。結論 ART妊婦の中でも融解胚移植妊娠はPPHのリスク因子になることが示唆された。融解胚移植妊娠については医師と速やかな医療連携がとれる体制の確立、及び将来的に院内助産分娩の対象から除外すべきか検討するための調査が必要と考える。(著者抄録)

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J02875&link_issn=&doc_id=20190107430008&doc_link_id=130007549960&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007549960&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

  27. Notch signaling enhances the mutual association with epithelial ovarian cancer and mesothelial cells

    Mai Sugiyama, Masato Yoshihara, Yoshihiro Koya, Akira Yokoi, Buntei Ryu, Fumitaka Kikkawa, Hiroaki Kajiyama

    CANCER SCIENCE   Vol. 109   page: 864 - 864   2018.12

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  28. Cancer-associated mesothelial cells as a potential therapeutic target in epithelial ovarian cancer

    Masato Yoshihara, Hiroaki Kajiyama, Mai Sugiyama, Yoshihiro Koya, Buntei Ryu, Akira Yokoi, Yusuke Yamamoto, Fumitaka Kikkawa

    CANCER SCIENCE   Vol. 109   page: 247 - 247   2018.12

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  29. RNA生物学の発展ががん研究にもたらしたもの 卵巣がんにおける細胞外RNAの関与(Progress in cancer research through RNA biology The role of extracellular RNAs in ovarian cancer) International journal

    横井 暁, 吉岡 祐亮, 山本 雄介, 松崎 潤太郎, 加藤 友康, 加藤 健, 梶山 広明, 吉川 史隆, 落谷 孝広

    日本癌学会総会記事   Vol. 77回   page: 231 - 231   2018.9

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  30. 上皮性卵巣癌における治療標的としての癌関連腹膜中皮細胞(Cancer-associated mesothelial cells as a potential therapeutic target in epithelial ovarian cancer) International journal

    吉原 雅人, 梶山 広明, 杉山 麻衣, 小屋 美博, 劉 文亭, 横井 暁, 山本 雄介, 吉川 史隆

    日本癌学会総会記事   Vol. 77回   page: 271 - 271   2018.9

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  31. 表層上皮性卵巣癌におけるNotchシグナルが及ぼす腹膜中皮細胞との微小環境形成への影響(Notch signaling enhances the mutual association with epithelial ovarian cancer and mesothelial cells) International journal

    杉山 麻衣, 吉原 雅人, 小屋 美博, 横井 暁, 劉 文亭, 吉川 史隆, 梶山 広明

    日本癌学会総会記事   Vol. 77回   page: 1351 - 1351   2018.9

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  32. 表層上皮性卵巣癌におけるNotchシグナルを介した腹膜中皮細胞の役割 International journal

    杉山 麻衣, 梶山 広明, 吉原 雅人, 小屋 美博, 横井 暁, 山下 守, 那波 明宏, 吉川 史隆

    日本産科婦人科学会雑誌   Vol. 70 ( 2 ) page: 857 - 857   2018.2

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  33. Carcinoma-associated mesothelial cells promote dissemination and platinum resistance in epithelial ovarian cancer.

    Masato Yoshihara, Hiroaki Kajiyama, Mai Sugiyama, Hiroaki Yasui, Yoshihiro Koya, Yoshihiko Yamakita, Buntei Ryu, Akira Yokoi, Yusuke Yamamoto, Fumitaka Kikkawa

    CANCER SCIENCE   Vol. 109   page: 118 - 118   2018.1

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  34. 【最新免疫学×周産期医学】基礎医学 免疫学の最初の一歩 細胞が放出する"エクソソーム"を対象とした新たな研究展開 International journal

    横井 暁, 落合 孝広

    周産期医学   Vol. 47 ( 12 ) page: 1539 - 1546   2017.12

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  35. 卵巣癌細胞由来悪性エクソソームによる腹膜播種性転移促進メカニズム International journal

    横井 暁, 吉岡 祐亮, 山本 雄介, 石川 光也, 加藤 友康, 清野 透, 梶山 広明, 吉川 史隆, 落谷 孝広

    日本癌学会総会記事   Vol. 76回   page: IS1 - 6   2017.9

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  36. 表層上皮性卵巣癌における癌関連中皮細胞と腫瘍進展およびプラチナ耐性獲得機構 International journal

    吉原 雅人, 梶山 広明, 杉山 麻衣, 安井 啓晃, 小屋 美博, 山北 由彦, 劉 文亭, 横井 暁, 山本 雄介, 吉川 史隆

    日本癌学会総会記事   Vol. 76回   page: E - 1054   2017.9

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  37. 血清中miRNAプロファイルによる早期卵巣がん診断バイオマーカーの開発 International journal

    横井 暁, 吉岡 祐亮, 加藤 友康, 梶山 広明, 吉川 史隆, 落谷 孝広

    日本分子腫瘍マーカー研究会誌   Vol. 32   page: 27 - 28   2017.3

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  38. 【Liquid biopsy】乳癌におけるエクソソーム研究 International journal

    横井 暁, 吉岡 祐亮, 落谷 孝広

    乳癌の臨床   Vol. 32 ( 1 ) page: 21 - 29   2017.2

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KAKENHI (Grants-in-Aid for Scientific Research) 6

  1. 腹腔内細胞コミュニケーションが誘導するオカルト播種の休眠維持環境構築のメカニズム

    Grant number:21K19562  2021.7 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    梶山 広明, 吉原 雅人, 横井 暁, 芳川 修久

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    Authorship:Coinvestigator(s) 

    本課題は腹腔内微小環境における癌関連腹膜中皮細胞に注目して、腹腔内オカルト播種の休眠の機能および維持メカニズムを追究する研究である。休眠の維持に関する解析項目に「腫瘍-CAMのNotchシグナル」や免疫回避の第一歩として「SDF-1α制御-腫瘍関連マクロファージ」との関連を取り入れた斬新かつ挑戦的な研究である。本課題で得られた知見によって腹膜全体をターゲットとした包括的治療戦略の策定や新規バイオマーカーの同定を目指す。特に腹膜は面積的に広範囲であるため、標的にしえた場合の治療及びQOL改善の効果も大きいと考えられる。さらに本研究は卵巣癌に限らず癌性腹膜炎を形成しうる他癌にも応用可能となりうる。

  2. 難治性卵巣がんにおける細胞外小胞機能解析と臨床応用基盤創生

    Grant number:21H03075  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    横井 暁, 梶山 広明, 山本 雄介, 吉田 康将

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    Authorship:Principal investigator 

    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    本研究は、卵巣がんにおけるエクソソームを始めとした細胞外小胞(Extracellular Vesicle: EV)を対象とし、EVが有する未だ明らかにされていない腫瘍生物学的意義を明らかにし、臨床応用へ向けた基盤となる知見を得ることを目的とします。未だ臨床的問題点が多く残る難治性卵巣がんにおけるEVの機能解明は極めて重要と考えられます。本研究では、①卵巣がん悪性化に関わるEVの機能解析 ②個別化医療を実現するEVバイオマーカーの創出 ③EVによる難治進行性卵巣がんの新規治療開発の、3点を軸に研究を展開し、卵巣がん患者予後の改善に繋が成果を得ることを目指します。

  3. Elucidating functional intratumoral heterogeneity by patient-derived cell culture system

    Grant number:21H02721  2021.4 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s) 

  4. 臨床応用へ向けたがん由来細胞外小胞の多様性および特異性の解明

    Grant number:20K22806  2020.9 - 2022.3

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

    横井 暁

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    Authorship:Principal investigator 

    Grant amount:\2860000 ( Direct Cost: \2200000 、 Indirect Cost:\660000 )

    本研究は、未だ明らかにされていないがん細胞由来細胞外小胞の多様性と、臨床応用へ向けた特性を明らかにすることを目的とする。研究代表者は、予後不良の卵巣がんを対象とし、血液、腹水、腫瘍組織等を用いて、細胞外小胞(Extracellular Vesicle: EV)抽出方法の検討、EV表面タンパク質のプロテオーム解析、EV関連核酸(RNAおよびDNA)の次世代シーケンスによる解析等を行うことで、臨床検体ベースの取り扱いの最適化、および特異マーカーの同定を行う。本研究で明らかになる知見は今後急速に進むと予想されるEVトランスレーショナル研究において、極めて重要な意義をもつ。
    本研究は、未だ明らかにされていないがん細胞由来細胞外小胞の多様性と、臨床応用へ向けた特性を明らかにすることを目的とする。あらゆる生細胞が恒常的に放出する、エクソソームをはじめとした細胞外小胞(Extracellular Vesicle: EV)は、過去10年程で世界的に研究が進み、研究領域としての地位を確固たるものとした。しかし、EV研究はその定義や取扱いが未だ議論の的になるほど発展途上であり、昨今でもそのアップデートが進んでいる。とりわけがん領域においては、ヒト体液サンプルを活用した研究が重要となるが、体液中EVの機能や臨床応用の可能性など、未だ明確な回答に辿りついたものはほぼ存在しない。本研究では、予後不良の卵巣がんを対象とし、血液、腹水、腫瘍組織等を用いて、EV抽出方法の検討、EV表面タンパク質のプロテオーム解析、EV関連核酸(RNAおよびDNA)の次世代シーケンスによる解析等を行うことで、臨床検体ベースの取り扱いの最適化、および特異マーカーの同定を行う。本年度は研究室の設営などを通して、必要な実験フローの整備を行った。また、種々の方法、種々の試料からエクソソーム、細胞外小胞を抽出し、タンパク質、核酸の抽出行いそのプロファイルを取得した。エクソソームを始めとしたいわゆるSmall-EVのみではなく、サイズの大きいLarge-EVの回収も同一検体より行い、その変化を検証した。もとより解析プラットフォームを有するシーケンサーは利用しており、種々の知見が得られている。EVの抽出に関連して、ナノテクノロジーの応用にも挑戦している。2021年度はこれまでのデータを基盤にその意義を深め、成果へとつなげる。
    2020年度はラボの設営という重要なステップがあったため、2021年度はより成果へつながる研究が展開できると考える。
    本研究に変更はなく、それを妨げる課題は現時点では特にない。予定通り、現在行っている患者体EVによるオミックス解析を継続する。本研究において主に対象とする卵巣がんは、極めて悪性度の高いがんであり、患者予後が悪く、サブタイプ等の多様性から、臨床に還元できる研究成果が得られにくいがん種である。しかし、その反面、臨床応用を目指した基礎的研究を行う意義は高いと言える。本研究は、需要の極めて高い、エクソソーム研究、卵巣がん研究の双方の発展に寄与する極めて重要な位置づけとなる。

  5. Elucidation of malignancy, peritoneal dissemination and spread mechanism of ovarian cancer by interaction with peritoneal mesothelium.

    Grant number:19H03797  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s) 

  6. Elucidation of peritoneal dissemination mechanism by exosome from ovarian cancer and development of new treatment

    Grant number:16K15704  2016.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    Kikkawa Fumitaka

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    Authorship:Coinvestigator(s) 

    We demonstrated that the exosome from ovarian cancer stimulated the peritoneal dissemination. By mouse model the exosome also prompted abdominal metastasis and causes morphological change in mesothelial cells. This phenomenon was caused by induction of apoptosis. We observed that the exosome increased MMP1 expression in mesothelial cells.
    Using clinical data base, we observed that MMP1 is an important prognostic marker and there are ovarian cancer patients with ascites including MMP1 mRNA.
    In conclusion, the exosome including MMP1 mRNA may be a prognostic biomarker and a treatment target for preventing abdominal metastasis.

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