Elucidation of peritoneal dissemination and exploration of novel therapeutics of ovarian cancer focusing on the morphological changes of spheroid-forming cell

• Project/Area Number: 18K16757
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Taguchi Ayumi 東京大学, 医学部附属病院, 助教 (60756782)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 卵巣癌 / 腹膜播種 / スフェロイド / KRAS / CXCL17 / 腫瘍内微小環境 / 分子標的薬 / 形態変化

Outline of Final Research Achievements

In vivo spheroid-formation was significantly increased in the KRAS-transfected ID8 cells (ID8-KRAS). Comprehensive cDNA microarray analysis revealed that some genes partially regulated by the MEK-ERK pathway were upregulated only in ID8-KRAS cells in 3D culture. A MEK inhibitor, trametinib, dramatically improved the prognosis for mice with ID8-KRAS tumors in an in vivo mouse model.
We next focused on a chemokine, CXCL17, which was upregulated in spheroid cells and established shRNA knockdown ID8-KRAS cells. shCXCL17-ID8-KRAS cells significantly suppressed peritoneal disseminations accompanied by the decreased number of peritoneal myeloid derived suppressor cells (MDSC).

Academic Significance and Societal Importance of the Research Achievements

本研究は、卵巣癌腹膜播種形成には腹腔内でのスフェロイド形成が重要であることを示し、また、KRAS変異がスフェロイドの安定化に寄与し、播種形成を促進することを見出した。スフェロイド形成を促進する遺伝子変異をターゲットとすることで、卵巣癌の播種進展を阻害できる可能性を示し、今後の卵巣癌治療方法の発展に寄与した。また、本研究は、がん遺伝子変異とその形態変化に伴うケモカインの発現変化が、腹腔内環境を調整し癌進展に関連している可能性を示した。この知見は、今後のがん遺伝子変異と腫瘍内微小環境を統合した治療戦略の開発に繋がる可能性がある。

Research Products

• [Journal Article] Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations (2019)
  • Author(s): Inoue Satoshi、Hirota Yasushi、Ueno Toshihide、十人省略、Tanaka Yosuke、Sakata Seiji、Takeuchi Kengo、Muraoka Ayako、Osuka Satoko、Saito Tsuyoshi、Oda Katsutoshi、Osuga Yutaka、Terao Yasuhisa、Kawazu Masahito、Mano Hiroyuki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41467-019-13708-y
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-17 is associated with expression of programmed cell death 1 ligand 1 in ovarian carcinoma. (2019)
  • Author(s): Aotsuka A, Matsumoto Y, Arimoto T, Kawata A, Ogishima J, Taguchi A, Tanikawa M, Sone K, Mori-Uchino M, Tsuruga T, Oda K, Kawana K, Osuga Y, Fujii T.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 10 Pages: 3068-3078
  • DOI: 10.1111/cas.14174
  • Peer Reviewed / Open Access
• [Journal Article] Endometriosis Triggers Excessive Activation of Primordial Follicles via PI3K-PTEN-Akt-Foxo3 Pathway (2019)
  • Author(s): Takeuchi Arisa、Koga Kaori、Satake Erina、Makabe Tomoko、Taguchi Ayumi、Miyashita Mariko、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Yoshino Osamu、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 104 Issue: 11 Pages: 5547-5554
  • DOI: 10.1210/jc.2019-00281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas. (2019)
  • Author(s): Kukita A, Sone K, Oda K, Hamamoto R, Kaneko S, Komatsu M, Wada M, Honjoh H, Kawata Y, Kojima M, Oki S, Sato M, Asada K, Taguchi A, Miyasaka A, Tanikawa M, Nagasaka K, Matsumoto Y, Wada-Hiraike O, Osuga Y, Fujii T
  • Journal Title: Biochem Biophys Res Commun Volume: in press Issue: 2 Pages: 30555-8
  • DOI: 10.1016/j.bbrc.2019.03.155
  • Peer Reviewed
• [Journal Article] A low albumin to globulin ratio with a high serum globulin level is a prognostic marker for poor survival in cervical cancer patients treated with radiation based therapy (2019)
  • Author(s): Yoshino Yasunori、Taguchi Ayumi、Shimizuguchi Takuya、Nakajima Yujiro、Takao Maki、Kashiyama Tomoko、Furusawa Akiko、Kino Nao、Yasugi Toshiharu
  • Journal Title: International Journal of Gynecologic Cancer Volume: 29 Issue: 1 Pages: 17-22
  • DOI: 10.1136/ijgc-2018-000025
  • Peer Reviewed
• [Journal Article] Lymphopenia after induction chemotherapy correlates with incomplete surgical resection in patients with advanced ovarian cancer (2018)
  • Author(s): Yoshino Yasunori、Taguchi Ayumi、Takao Maki、Kashiyama Tomoko、Furusawa Akiko、Uno Masaya、Okada Satoshi、Kino Nao、Yasugi Toshiharu
  • Journal Title: International Journal of Clinical Oncology Volume: 24 Issue: 4 Pages: 428-436
  • DOI: 10.1007/s10147-018-1374-4
  • Peer Reviewed
• [Journal Article] The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway. (2018)
  • Author(s): Ogishima J, Taguchi A, Kawata A, Kawana K, Yoshida M, Yoshimatsu Y, Sato M, Nakamura H, Kawata Y, Nishijima A, Fujimoto A, Tomio K, Adachi K, Nagamatsu T, Oda K, Kiyono T, Osuga Y, Fujii T
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1-13
  • DOI: 10.1186/s12885-018-4922-4
  • Peer Reviewed / Open Access
• [Journal Article] Intraperitoneal neutrophils activated by KRAS-induced ovarian cancer exert antitumor effects by modulating adaptive immunity. (2018)
  • Author(s): Yoshida M, Taguchi A, Kawana K, Ogishima J, Adachi K, Kawata A, Nakamura H, Sato M, Fujimoto A, Inoue T, Tomio K, Mori M, Nagamatsu T, Arimoto T, Koga K, Hiraike OW, Oda K, Kiyono T, Osuga Y, Fujii T
  • Journal Title: Int J Oncol Volume: 53 Pages: 1580-1590
  • DOI: 10.3892/ijo.2018.4504
  • Peer Reviewed
• [Presentation] CXCL10 works as a tumor promoter in tumor microenvironment in ovarian cancer (2018)
  • Author(s): 荻島樹里、田口歩、川名敬、吉田光代、河田啓、佐藤雅和、冨尾賢介、足立克之、永松健、織田克利、大須賀穣、藤井知行
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] CXCL17, as a key regulator of microenvironment, promotes peritoneal dissemination in ovarian cancer (2018)
  • Author(s): 河田 啓、田口 歩、荻島 樹里、吉田 光代、中村 寛江、佐藤 雅和、冨尾 賢介、足立 克之、織田 克利、川名 敬、大須賀 穣、藤井 知行
  • Organizer: 第70回 日本産科婦人科学会 学術講演会