Initial steps of high-grade serous ovarian carcinoma carcinogenesis

• Project/Area Number: 17K16851
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Keio University (2019); Shimane University (2017-2018)
• Principal Investigator: NAKAMURA Kohei 慶應義塾大学, 医学部(信濃町), 特任助教 (10775802)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 卵巣癌 / ゲノム / STIC / 発癌 / 遺伝子変異 / TP53 / 漿液性卵巣癌 / 全エクソン解析 / 発癌機構 / 婦人科腫瘍学 / 卵巣がん / 発がん機構 / 低悪性度卵巣腫瘍

Outline of Final Research Achievements

We identified two patterns of three genetic alterations (i.e., p53/KRASV12/c-Myc and p53/KRASV12/PI3K-AKT) that were essential for HGSOC development, and successfully established an in vitro step-wise model of carcinogenesis using immortalized FTSECs. Furthermore, we identified the signal transduction in STICs and demonstrated that the hormone exposure to fimbriae in ovulation contributes to the initial steps of HGSOC carcinogenesis. Regarding LGSOC carcinogenesis, we demonstrated that the exposure of content fluid of serous cystadenoma to OSE causes the NFkB activation and contributes to the initial steps of LGSOC carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

卵巣高悪性度漿液性癌の卵管上皮起源説が注目されている。我々はSTICにおけるシグナル異常の同定を行い、 卵管采への排卵時の卵胞液による刺激がHGSOC発癌の初期段階に関与している可能性を示した。また、卵巣高悪性度漿液性癌についてはOSEへの漿液性卵巣嚢腫内容液曝露が発癌メカニズムに寄与している可能性を示した。
本研究で得られる成果は世界における卵巣癌発生の起源を分子レベルで解決し得るツールとなる点で意義深いものになると推測される。さらには、卵巣癌の初期発癌機構を解明することで、新規分子標的治療薬の開発にもつながると期待される。

Research Products

• [Journal Article] The fallopian tube as origin of ovarian cancer: Change of diagnostic and preventive strategies. (2020)
  • Author(s): Satoru Kyo, Noriyoshi Ishikawa, Kohei Nakamura, Kentaro Nakayama
  • Journal Title: Cancer medicine Volume: 9 Issue: 2 Pages: 421-431
  • DOI: 10.1002/cam4.2725
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma (2020)
  • Author(s): Nakamura Kohei、Aimono Eriko、Tanishima Shigeki、Imai Mitsuho、Nagatsuma Akiko Kawano、Hayashi Hideyuki、Yoshimura Yuki、Nakayama Kentaro、Kyo Satoru、Nishihara Hiroshi
  • Journal Title: Diagnostics Volume: 10 Issue: 4 Pages: 200-200
  • DOI: 10.3390/diagnostics10040200
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Olaparib Monotherapy for BRIP1-Mutated High-Grade Serous Endometrial Cancer (2020)
  • Author(s): Kohei Nakamura, Eriko Aimono, Shigeki Tanishima, Mitsuho Imai, Akiko Kawano Nagatsuma, Hideyuki Hayashi, Yuki Yoshimura, Kentaro Nakayama, Satoru Kyo, and Hiroshi Nishihara,
  • Journal Title: JCO Precision Oncology Volume: - Issue: 4 Pages: 283-290
  • DOI: 10.1200/po.19.00368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies). (2019)
  • Author(s): Ruriko Ono, Kentaro Nakayama, Kohei Nakamura, Hitomi Yamashita, Tomoka Ishibashi, Masako Ishikawa, Toshiko Minamoto, Sultana Razia, Noriyoshi Ishikawa, Yoshiro Otsuki, Satoru Nakayama, Hideyuki Onuma, Hiroko Kurioka, Satoru Kyo
  • Journal Title: International journal of molecular sciences Volume: 20 Issue: 15 Pages: 1-1
  • DOI: 10.3390/ijms20153744
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological and biological analysis of PIK3CA mutation and amplification in cervical carcinomas. (2019)
  • Author(s): Sultana Razia, Kentaro Nakayama, Kohei Nakamura, Tomoka Ishibashi, Masako Ishikawa, Toshiko Minamoto, Kouji Iida, Yoshiro Otsuki, Satoru Nakayama, Noriyoshi Ishikawa, Satoru Kyo
  • Journal Title: Experimental and therapeutic medicine Volume: 18 Pages: 2278-2284
  • DOI: 10.3892/etm.2019.7771
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship between Microsatellite Instability, Immune Cells Infiltration, and Expression of Immune Checkpoint Molecules in Ovarian Carcinoma: Immunotherapeutic Strategies for the Future. (2019)
  • Author(s): Hitomi Yamashita, Kentaro Nakayama, Masako Ishikawa, Tomoka Ishibashi, Kohei Nakamura, Kiyoka Sawada, Yuki Yoshimura, Nagisa Tatsumi, Sonomi Kurose, Toshiko Minamoto, Kouji Iida, Sultana Razia, Noriyoshi Ishikawa, Satoru Ky
  • Journal Title: International journal of molecular sciences Volume: 20 Issue: 20 Pages: 1-1
  • DOI: 10.3390/ijms20205129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sarcopenic Factors May Have No Impact on Outcomes in Ovarian Cancer Patients (2019)
  • Author(s): Nakayama Naomi、Nakayama Kentaro、Nakamura Kohei、Razia Sultana、Kyo Satoru
  • Journal Title: Diagnostics Volume: 9 Issue: 4 Pages: 206-206
  • DOI: 10.3390/diagnostics9040206
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Frequency of PIK3CA Mutations in Low-Grade Serous Ovarian Carcinomas of Japanese Patients. Diagnostics (Basel). 2019;27;10(1). pii: E13. (2019)
  • Author(s): Ishibashi T, Nakayama K, Razia S, Ishikawa M, Nakamura K, Yamashita H, Dey P, Iida K, Kurioka H, Nakayama S, Otsuki Y, Ishikawa N, Kyo S.
  • Journal Title: Diagnostics (Basel). Volume: 27;10(1) Issue: 1 Pages: 13-13
  • DOI: 10.3390/diagnostics10010013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High frequency of POLE mutations in synchronous endometrial and ovarian carcinoma. (2018)
  • Author(s): Ishikawa M, Nakayama K＊, Nakamura K, Ono R, Yamashita H, Ishibashi T, Minamoto T, Iida K, Razia S, Ishikawa N, Kyo S.
  • Journal Title: Hum Pathol Volume: 18 Pages: 30424-30426
  • DOI: 10.1016/j.humpath.2018.11.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ultrasound-guided intranodal lymphangiography with lipiodol for treatment of chylous ascites following surgery for ovarian cancer: A case report (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Minamoto Toshiko、Ishibashi Tomoka、Ohnishi Kaori、Yamashita Hitomi、Ono Ruriko、Sasamori Hiroki、Razia Sultana、Kamrunnahar Shanta、Ishikawa Masako、Kyo Satoru
  • Journal Title: Molecular and Clinical Oncology Volume: 9 Pages: 178-180
  • DOI: 10.3892/mco.2018.1647
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic significance of pre?treatment neutrophil?to?lymphocyte and platelet?to?lymphocyte ratios in non?surgically treated uterine cervical carcinoma (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Tatsumi Nagisa、Minamoto Toshiko、Ishibashi Tomoka、Ohnishi Kaori、Yamashita Hitomi、Ono Ruriko、Sasamori Hiroki、Razia Sultana、Kamrunnahar Shanta、Ishikawa Masako、Kyo Satoru
  • Journal Title: Molecular and Clinical Oncology Volume: 9 Pages: 138-144
  • DOI: 10.3892/mco.2018.1646
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic analysis and phosphoinositide???3?kinase/protein kinase B signaling pathway status in ovarian endometrioid borderline tumor samples (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Ishikawa Masako、Minamoto Toshiko、Ishibashi Tomoka、Sato Emi、Sanuki Kaori、Yamashita Hitomi、Ono Ruriko、Iida Kouji、Sultana Razia、Hossain Mohammad、Ishikawa Noriyoshi、Kyo Satoru
  • Journal Title: Oncology Letters Volume: 16 Pages: 189-194
  • DOI: 10.3892/ol.2018.8626
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ARID1B as a Potential Therapeutic Target for ARID1A-Mutant Ovarian Clear Cell Carcinoma (2018)
  • Author(s): Sato Emi、Nakayama Kentaro、Razia Sultana、Nakamura Kohei、Ishikawa Masako、Minamoto Toshiko、Ishibashi Tomoka、Yamashita Hitomi、Iida Kouji、Kyo Satoru
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 6 Pages: 1710-1710
  • DOI: 10.3390/ijms19061710
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preoperative tumor size is associated with deep myometrial invasion and lymph node metastases and is a negative prognostic indicator for patients with endometrial carcinoma (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Ishikawa Noriyoshi、Minamoto Toshiko、Ishibashi Tomoka、Ohnishi Kaori、Yamashita Hitomi、Ono Ruriko、Sasamori Hiroki、Razia Sultana、Hossain Mohammad Mahmud、Kamrunnahar Shanta、Ishikawa Masako、Kyo Satoru
  • Journal Title: Oncotarget Volume: 9 Issue: 33 Pages: 23164-23172
  • DOI: 10.18632/oncotarget.25248
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Minamoto Toshiko、Ishibashi Tomoka、Ohnishi Kaori、Yamashita Hitomi、Ono Ruriko、Sasamori Hiroki、Razia Sultana、Hossain Mohammad Mahmud、Kamrunnahar Shanta、Ishikawa Masako、Ishikawa Noriyoshi、Kyo Satoru
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 4 Pages: 979-979
  • DOI: 10.3390/ijms19040979
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GnRH agonist pre-treatment for microwave endometrial ablation in women with less than 1 centimetre myometrial thickness (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Ishikawa Masako、Katagiri Atsuko、Katagiri Hiroshi、Ishibashi Tomoka、Sato Emi、Kyo Satoru
  • Journal Title: Journal of Obstetrics and Gynaecology Volume: 21 Issue: 8 Pages: 1-3
  • DOI: 10.1080/01443615.2018.1436163
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High preoperative Glasgow prognostic score is a negative prognostic factor for patients with endometrial carcinoma (2018)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Minamoto Toshiko、Ishibashi Tomoka、Sanuki Kaori、Yamashita Hitomi、Ono Ruriko、Sasamori Hiroki、Komatsu?Fujii Takayoshi、Ishikawa Masako、Kyo Satoru
  • Journal Title: Molecular and Clinical Oncology Volume: 8 Pages: 429-433
  • DOI: 10.3892/mco.2018.1551
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial cells (2017)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Ishikawa Noriyoshi、Ishikawa Masako、Sultana Razia、Kiyono Tohru、Kyo Satoru
  • Journal Title: Oncotarget Volume: 9 Issue: 16 Pages: 12609-12619
  • DOI: 10.18632/oncotarget.23035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term outcomes of microwave endometrial ablation for treatment of patients with menorrhagia: A retrospective cohort study (2017)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Sanuki Kaori、Minamoto Toshiko、Ishibashi Tomoka、Sato Emi、Yamashita Hitomi、Ishikawa Masako、Kyo Satoru
  • Journal Title: Oncology Letters Volume: 14 Pages: 7783-7790
  • DOI: 10.3892/ol.2017.7208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 低悪性度漿液性癌の発癌過程におけるOSEの卵管上皮化生について (2018)
  • Author(s): 中村康平
  • Organizer: 第61回日本婦人科腫瘍学会学術講演会
• [Presentation] 低悪性度漿液性癌の発癌過程におけるOSEの卵管上皮化生について (2018)
  • Author(s): 中村康平
  • Organizer: 第71回日本産科婦人科学会
• [Presentation] 卵巣がんのoriginについて (2018)
  • Author(s): 中村康平
  • Organizer: 新潟産婦人科シンポジウム
  • Invited
• [Presentation] Serous tubal intraepithelial carcinoma (STIC) モデル細胞株を用いた卵巣高悪性度漿液性癌の発癌初期のシグナル異常の解析 (2017)
  • Author(s): 中村 康平
  • Organizer: 日本産婦人科学会
• [Presentation] 卵管采上皮分泌不死化細胞株を用いた卵巣高悪性度漿液性癌の癌化モデル作成と発癌分子機構の解析 (2017)
  • Author(s): 中村 康平
  • Organizer: 日本癌学会
• [Presentation] 子宮内膜症によるダグラス窩完全閉塞症例に対するTLH―逆行性子宮全摘出術の導入― (2017)
  • Author(s): 中村 康平
  • Organizer: 婦人科内視鏡学会
• [Presentation] 漿液性嚢胞腺腫の起源について -低悪性度漿液性癌の発癌機構の解明に向けて- (2017)
  • Author(s): 中村 康平
  • Organizer: 3大学コンソーシアム
• [Presentation] Successful reconstitution of high-grade serous ovarian carcinoma in vivo from primary fallopian tube secretory epithelial cells (2017)
  • Author(s): 中村 康平
  • Organizer: AACR Annual Meeting
  • Int'l Joint Research
• [Book] 臨牀と研究 (2020)
  • Author(s): 中村康平、西原広史
  • Total Pages: 7
  • Publisher: 大道学館出版部