Study for novel treatment of gynecological cancer stem cells based on specific metabolism

• Project/Area Number: 18K09250
• 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: Niigata University
• Principal Investigator: Ishiguro Tatsuya 新潟大学, 医歯学総合病院, 助教 (80625690)
• Co-Investigator(Kenkyū-buntansha): 榎本 隆之 新潟大学, 医歯学系, 教授 (90283754)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); 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: 子宮体癌 / 卵巣がん / がん幹細胞 / 解糖系 / 子宮体がん

Outline of Final Research Achievements

Uterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. A high level of ALDH correlated with activation of the glycolytic pathway. Blockade of glucose transporter 1 (GLUT1) inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

Academic Significance and Societal Importance of the Research Achievements

現在年間約1万人の国内新規患者を認める子宮体癌において，保険収載され臨床使用されている抗がん剤は少なく，手術摘出困難な進行例における治療は難渋することが多い。申請者らが今回報告した特異的阻害剤の有効性に関する研究成果は，子宮体癌の新たな治療戦略として大いに期待される。
今回の研究成果は，Stem Cell Reports誌の表紙に選出され，また2019年度日本産科婦人科学会優秀論文賞に選定された。加えて，臨床ニュースに取り上げられ，全国の子宮体癌患者様より実臨床への応用に向けた期待の声をいただいている。

Research Products

• [Journal Article] Establishment of in vitro 3D spheroid cell cultivation from human gynecologic cancer tissues (2021)
  • Author(s): Ueda Haruka、Mori Yutaro、Yamawaki Kaoru、Ishiguro Tatsuya、Ohata Hirokazu、Sato Ai、Sugino Kentaro、Yachida Nozomi、Yamaguchi Manako、Suda Kazuaki、Tamura Ryo、Yoshihara Kosuke、Okamoto Koji、Enomoto Takayuki
  • Journal Title: STAR Protocols Volume: 2 Issue: 1 Pages: 100354-100354
  • DOI: 10.1016/j.xpro.2021.100354
  • Peer Reviewed / Open Access
• [Journal Article] ALDH-dependent glycolytic activation mediates stemness and Paclitaxel resistance in patient-derived spheroid models of uterine endometrial cancer (2019)
  • Author(s): Mori Y, Yamawaki K, Ishiguro T, Yoshihara K, Ueda H, Sato A, Ohata H, Yoshida Y, Minamino T, Okamoto K, Enomoto T
  • Journal Title: Stem Cell Reports Volume: 13 Issue: 4 Pages: 730-730
  • DOI: 10.1016/j.stemcr.2019.08.015
  • Peer Reviewed / Open Access