Analysis of the pathogenesis of endometriosis focusing on intracellular communications.

• Project/Area Number: 26670725
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: Sawada Kenjiro 大阪大学, 医学系研究科, 講師 (00452392)
• Research Collaborator: Nakamura Koji ; Sawada Ikuko ; Yoshimura Akihiko
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 子宮内膜症 / エクソソーム / 腹膜中皮細胞 / CD44 / 細胞間情報伝達 / 上皮間葉移行 / 卵巣

Outline of Final Research Achievements

The overcome of endometriosis is a critical issue to improve quality of life of women. As a pathogenesis, it is well accepted that endometriosis is a process produced by menstrual debris including endometrial tissue that escapes retrograde through fallopian tubes into pelvis. Thus, we hypothesized endometrial cells evolve to “endometriosis cells” during retrograde menstruation by receiving some information from cells located at fallopian tubes or peritoneal walls. Herein, we focused on exosomes produced from cells as an intracellular communication tool and intended to analyze the role of exosomes. As an initial step, exosomes were isolated from ovarian cancer cells. Exosomes were co-cultured with human peritoneal mesothelial cells (HPMCs) which internalized the exosomes. CD44, which was enriched in exosomes, transferred to HPMCs upon internalization, leading to high levels of CD44 in HPMCs membrane. We showed one possible role of exosomes as an intracellular communication tool.

Research Products

• [Journal Article] Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells. (2017)
  • Author(s): Nakamura, K. Sawada, K. Kinose, Y. Yoshimura, A. Toda, A. Nakatsuka, E. Hashimoto, K. Mabuchi, S. Morishige, KI. Kurachi, H. Lengyel, E. Kimura, T.
  • Journal Title: Mol Cancer Res Volume: 15(1) Issue: 1 Pages: 78-92
  • DOI: 10.1158/1541-7786.mcr-16-0191
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical relevance of circulating cell-free microRNAs in ovarian cancer. (2016)
  • Author(s): Nakamura, K. Sawada, K. Yoshimura, A. Kinose, Y. Nakatsuka, E. Kimura, T.
  • Journal Title: Mol Cancer Volume: 24;15(1) Issue: 1 Pages: 48-48
  • DOI: 10.1186/s12943-016-0536-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft ModelMice. (2016)
  • Author(s): Sawada, I. Hashimoto, K. Sawada, K. Kinose, Y. Nakamura, K. Toda, A. Nakatsuka, E. Yoshimura, A. Mabuchi, S. Fujikawa, T. Itai, A. Kimura, T.
  • Journal Title: Int J Gynecol Cancer Volume: 26(4) Issue: 4 Pages: 610-618
  • DOI: 10.1097/igc.0000000000000668
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Inhibitor of κB Kinase β Prevents Inflammation-Induced Preterm Delivery by Inhibiting IL-6 Production from Amniotic Cells. (2016)
  • Author(s): Toda, A. Sawada, K. Fujikawa, T. Wakabayashi, A. Nakamura, K. Sawada, I. Yoshimura, A. Nakatsuka, E. Kinose, Y. Hashimoto, K. Mabuchi, S. Tokuhira, A. Nakayama, M. Itai, A. Kurachi, H. Kimura, T.
  • Journal Title: Am J Pathol Volume: 186(3) Pages: 616-629
  • Peer Reviewed / Open Access
• [Journal Article] Is the exosome a potential target for cancer immunotherapy? (2016)
  • Author(s): Yoshimura, A. Sawada, K. Kimura, T.
  • Journal Title: Ann Transl Med Volume: 5(5) Issue: 5 Pages: 117-117
  • DOI: 10.21037/atm.2017.01.47
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of raloxifene hydrochloride for the prevention of health care problems in patients who undergo surgery for endometrial cancer: a multicenter randomized clinical trial. (2015)
  • Author(s): Nakamura, K. Sawada, K. Sugiyama, M. Mabuchi, S. Hisamatsu, T. Nishio, Y. Ito, K. Kimura, T. Kamiura, S. Morishige, K.
  • Journal Title: Int J Gynecol Cancer Volume: 25 Issue: 2 Pages: 288-295
  • DOI: 10.1097/igc.0000000000000333
  • Peer Reviewed / Open Access
• [Journal Article] IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Anti-angiogenic Treatment (2015)
  • Author(s): Kinose, Y. Sawada, K. Makino, H. Ogura, T. Mizuno, T. Suzuki, N. Fujikawa, T. Morii, E. Nakamura, K. Sawada, I. Toda, A. Hashimoto, K. Isobe, A. Mabuchi, S. Ohta, T. Itai, A. Morishige, K. I. Kurachi, H. Kimura, T
  • Journal Title: Mol Cancer Ther Volume: 14 Issue: 4 Pages: 909-19
  • DOI: 10.1158/1535-7163.mct-14-0696
  • Peer Reviewed / Open Access
• [Presentation] 婦人科悪性腫瘍治療後の卵巣機能喪失により生じる不定愁訴に対する漢方薬治療の可能性の検討 (2016)
  • Author(s): 吉村明彦 澤田健二郎 笹野智之 小笹勝巳 黒田浩正 中塚えりか 中村幸司 木瀬康人 木村正
  • Organizer: 第31回日本女性医学学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-11-05
• [Presentation] Elevated level of serum miR-99a is correlated with serous epithelial ovarian cancer and can be a potential biomarker. (2016)
  • Author(s): Yoshimura, A. Sawada, K. Nakamura, K. Kinose, Y. Nakatsuka, E. Mabuchi, S. Kimura, T.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Elevated level of circulating microRNA-99a correlates with serous epithelial ovarian cancer and can be used as a potential biomarker. (2016)
  • Author(s): Yoshimura, A. Sawada, K. Nakamura, K. Kinose, Y. Nakatsuka, E. Mabuchi, S. Kimura, T.
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-21
• [Presentation] Elevated level of circulating microRNA-99a is correlated with serous epithelial ovarian cancer and can be used as a potential biomarker. (2016)
  • Author(s): Yoshimura, A. Sawada, K. Nakamura, K. Kinose, Y. Nakatsuka, E. Mabuchi, S. Kimura, T.
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Ovarian cancer cells promote cancer invasion by transferring CD44 to mesothelial cells via exosomes. (2015)
  • Author(s): Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Erika Nakatsuka, Akihiko Yoshimura, Seiji Mabuchi, Tadashi Kimura
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 卵巣がんにおけるPAI-1(プラスミノーゲン活性化抑制因子1)の発現の解析及び新規阻害剤の治療応用への可能性の検討 (2015)
  • Author(s): 中塚 えりか、澤田 健二郎、中村 幸司、吉村 明彦、木瀬 康人、馬淵 誠士、木村 正
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Ovarian cancer exosomes promote invasion by affecting mesothelial cells through the upregulation of MMP9 secretion and mesothelial cell barrier. (2015)
  • Author(s): Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura
  • Organizer: 第57回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 盛岡
  • Year and Date: 2015-08-07
• [Presentation] Exosome transfer from ovarian cancer cells to mesothelial cells promotes cell invasion by upregulating MMP-9 secretion and increasing clearance of mesothelial cells. (2015)
  • Author(s): Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura.
  • Organizer: American Association for Cancer Research Annual Meeting 2015
  • Place of Presentation: America, Pennsylvania
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] 卵巣癌細胞由来exosome の腹膜中皮細胞への情報伝達機構の解明―癌細胞由来CD44 はexosome により中皮細胞に移行し，腹膜中皮のMMP 9 分泌促進，Ecadherin 発現抑制を誘導し腹膜播種を促進する (2015)
  • Author(s): 中村幸司 澤田健二郎 木瀬康人 吉村明彦 中塚えりか 戸田有朱香 橋本香映 馬淵誠士 木村正
  • Organizer: 第6７回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2015-04-09
• [Presentation] 卵巣がんにおけるPAI 1（プラスミノーゲン活性化抑制因子1）の発現の検討とその阻害剤の抗がん治療への可能性の検討 (2015)
  • Author(s): 中塚えりか 澤田健二郎 中村幸司 吉村明彦 木瀬康人 澤田育子 戸田有朱香 馬淵誠士 木村正
  • Organizer: 第6７回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2015-04-09
• [Presentation] Targeting inhibitor of NF-κb kinase beta (IKKβ) may represent a possible novel treatment for endometriosis (2014)
  • Author(s): Sawada, I. Hashimoto, K. Sawada, K. Fujikawa, T. Itai, A. Kimura, T.
  • Organizer: Endocrine Society’s 96th Annual Meeting and Expo
  • Place of Presentation: Chicago, U.S.A.
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] 子宮内膜症に対する新規低分子IKK阻害剤(IMD-0560)の効果の検討 (2014)
  • Author(s): 澤田育子. 橋本香映. 木瀬康人. 戸田有朱香. 中村幸司. 澤田健二郎. 木村 正
  • Organizer: 第66回日本産科婦人科学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-18 – 2014-04-20