Role of angiogenesis and its inhibition in the surrounding myometrium for the development of uterine leiomyoma

• Project/Area Number: 18K09219
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Chiba University
• Principal Investigator: Ishikawa Hiroshi 千葉大学, 大学院医学研究院, 講師 (70553973)
• Co-Investigator(Kenkyū-buntansha): 生水 真紀夫 千葉大学, 大学院医学研究院, 教授 (30226302)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 子宮筋腫 / 血管内皮成長因子 / 低酸素 / 血管内皮増殖因子 / 低酸素誘導因子 / 子宮筋 / VEGF / xenograftモデル / 血管新生

Outline of Final Research Achievements

We identified the highest expression of mRNA of vascular endothelial growth factor (VEGF) and its receptors, VEGFR1 and VEGFR2, in myometrial tissues surrounding uterine leiomyoma, so called leiomyoma pseudocapsule, compared with that in normal myometrium and uterine leiomyoma, suggesting that angiogenesis in the leiomyoma pseudocapsule may play important roles for the blood supply to the leiomyoma. We also identified the growth of leiomyoma xenograft was significantly inhibited by the administration of the inhibitors of hypoxia-inducible factor-1(HIF-1), which expression is higher in uterine leiomyoma than that in myometrium, in non-obese diabetes/severe combined immunodeficient mice. Because inhibition of angiogenesis in the leiomyoma pseudocapsule may induce downregulation of HIF-1 in uterine leiomyoma, these results suggest that inhibition of HIF-1 is a potential therapeutic strategy for the treatment of uterine leiomyoma.

Academic Significance and Societal Importance of the Research Achievements

子宮筋腫は産婦人科で最も多い腫瘍で、女性の3人に1人が罹患すると言われているが、その病態はいまだ解明されていない。現在の子宮筋腫に対する薬物療法は女性ホルモンの作用を遮断してしまうため、6か月以上の長期間の投与が認められておらず、新しい治療法の開発が求められている。
本研究で明らかとなった子宮筋腫周囲筋層の血管新生阻害効果は、女性のホルモンバランスを崩さない新しい子宮筋腫の治療法の開発につながると考えられる。

Research Products

• [Journal Article] Torsion of a Large Myomatous Uterus Associated with Progressive Renal Failure and Paralytic Ileus in an 86-Year-Old Woman. (2019)
  • Author(s): Wang G, Ishikawa H, Sato A, Shozu M
  • Journal Title: Case Rep Obstet Gynecol Volume: - Pages: 1-5
  • DOI: 10.1155/2019/1601368
  • Peer Reviewed / Open Access
• [Presentation] VEGF and VEGF receptor expression in pseudocapsule of uterine leiomyoma (2021)
  • Author(s): Yanruo Zhou, Hiroshi Ishikawa, Taichi Wake, Tetsuji Nishiwaki, Makio Shozu
  • Organizer: 第73回日本産科婦人科学会学術講演会
• [Presentation] 子宮筋腫の薬物療法-GnRHアンタゴニストの使用経験を含めて- (2019)
  • Author(s): 石川博士
  • Organizer: 水戸臨床婦人科懇話会
• [Presentation] 子宮筋腫の薬物療法 -働く女性のQOL向上をめざして- (2019)
  • Author(s): 石川博士
  • Organizer: 第24回日本女性医学会ワークショップ
  • Invited
• [Presentation] 産婦人科における黄体ホルモン療法 -妊娠合併症から子宮がんまで- (2019)
  • Author(s): 石川博士
  • Organizer: 第92回日本内分泌学会
• [Presentation] Inhibition of HIF-1 blocks uterine leiomyoma growth both in vitro and in vivo. (2019)
  • Author(s): Ishikawa H, Xu L, Kobayashi T, Shozu M
  • Organizer: 5th ,Congress of SEUD, Society of endometriosis and uterine disorders
• [Presentation] Inhibition of HIF-1 using echinomycin inhibits cell proliferation and induces apoptosis in uterine leiomyoma. (2019)
  • Author(s): Ishikawa H, Nishiwaki T, Shozu M
  • Organizer: 第71回日本産科婦人科学会
• [Remarks]
  • URL: https://www.m.chiba-u.ac.jp/dept/gynecol/research/group/seisyoku/