Cancer stemness and postoperative peritoneal recurrence in intraperitoneally spilled-cancer cells during surgery

• Project/Area Number: 18K16352
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Kodama Hirokazu 滋賀医科大学, 医学部, 医員 (20581929)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 術後がん再発 / 腹膜転移 / 癌幹細胞 / 手術炎症 / CD44 / 腹膜播種 / 手術誘導転移 / 脱分化 / 炎症 / 抗CD44抗体治療 / がん幹細胞 / 転移能 / 術後再発 / 多能性マーカー

Outline of Final Research Achievements

To elucidate part of the mechanism by which intraperitoneal cancer cells form peritoneal metastases, especially focusing on cancer stem-like cells that were spilled intraperitoneally during gastric cancer surgery, we investigated the followings, 1) stemness of CD44-positive cancer cells, 2) tumorigenicity of CD44-positive cancer stem-like cells, and 3) tumorigenicity of intraperitoneal gastric cancer cells in a surgical inflammatory environment.
The CD44-positive gastric cancer cells possessed cancer stem cell properties that showed pluripotency, differentiation ability into CD44-negative gastric cancer cells, and tumorigenicity. On the other hand, CD44-negative cells had plasticity that changed to CD44-positive cells in the peritoneal environment. In particular, surgical peritoneal inflammation was thought to change CD44-negative cells into CD44-positive cells and impart peritoneally metastatic potential.

Academic Significance and Societal Importance of the Research Achievements

本研究結果から、術中腹腔内散布されるCD44陽性胃癌細胞は癌幹細胞様細胞の性質を持ち、術後腹膜再発形成する重要な癌細胞であるため、術後腹膜再発を防ぐための治療ターゲットをCD44陽性腹腔内癌細胞だと考え、再発予防戦略が構築されていくであろう。
また、手術時炎症がCD44陰性の分化がん細胞をCD44陽性がん幹細胞様細胞へと変化させ、腹膜再発を促進させる事がわかり、手術時炎症のコントロールも腹膜再発予防の重要な戦略要素となるであろう。

Research Products

• [Presentation] Therapeutic strategy based on the mechanism of peritoneal relapse after surgery for gastric cancer (2020)
  • Author(s): Satoshi Murata, Katsushi Takebayashi, Tsuyoshi Yamaguchi, Sachiko Kaida, Ken Ishikawa, Hirokazu Kodama, Miyuki Shimoji, Andreas Michael Sihombing, Masatsugu Kojima, Toru Miyake, Hiroya Iida, Tomoyuki Ueki, Mina Kitamura, Aya Tokuda, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] CD44-enriched cancer stem-like cells as a source of peritoneal metastasis from gastric cancer (2020)
  • Author(s): Andreas Michael Sihombing, Satoshi Murata, Miyuki Shimoji, Katsushi Takebayashi, Hirokazu Kodama, Masatsugu Kojima, Tomoyuki Ueki, Naomi Kitamura, Mina Kitamura, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Effect of hyperthermia on the cancer stem-like cells (2020)
  • Author(s): Miyuki Shimoji, Satoshi Murata, Andreas Michael Sihombing, Katsushi Takebayashi, Hirokazu Kodama, Masatsugu Kojima, Tomoyuki Ueki, Naomi Kitamura, Mina Kitamura, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Tumor Ag-specific CTL generation from tumor-associated lymphocytes in malignant ascites of peritoneal metastases (2020)
  • Author(s): Masatsugu Kojima, Satoshi Murata, Miyuki Shimoji, Andreas Michael Sihombing, Naomi Kitamura, Tomoyuki Ueki, Mina Kitamura, Katsushi Takebayashi, Hirokazu Kodama, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会