Targeted inhibition of Tim-3-positive tumor-associated macrophages suppresses tumorigenicity of cancer cells

• Project/Area Number: 18K07287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Hokkaido University
• Principal Investigator: Yoneda Akihiro 北海道大学, 産学・地域協働推進機構, 特任助教 (00451419)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腫瘍マクロファージ / 幹細胞様特性 / 癌幹細胞

Outline of Final Research Achievements

The purpose of the present study was to determine whether tumor-associated macrophages (TAMs) induce a stem cell property of cancer cells and promote the tumorigenicity of cancer cells. We showed that a small population of TAMs expressed Tim-3 and Tim-3-positive TAMs induced the stem cell property of cancer cells. Cancer cells co-cultured with Tim-3-positive TAMs have a high tumorigenic potential. We also identified three candidate factors concerning an induction of stem cell property. Silencing of three candidate factors in Tim-3-positive TAMs inhibited the induction of stem cell property for cancer cells. These results suggest that TAMs is involved in the induction of stem cell property and tumorigenic potential of cancer cells.

Academic Significance and Societal Importance of the Research Achievements

膵癌などの難治性固形癌は、現状の治療法では十分な完治が見込めないことから、さらなる新規治療法の開発が急務である。特に、腫瘍細胞が獲得する抗癌剤抵抗性の解明は、新規治療法の開発において重要な課題となっている。本申請研究では、腫瘍マクロファージ（TAMs）が腫瘍細胞に幹細胞様特性を付与することを明らかとした。この結果は、今後、難治性癌のもつ抗癌剤抵抗性解除を目的とした新規治療法の開発において、貴重な知見を提供し、現行の治療法をより効果的にするための重要な糸口を提供するものといえ、学術的および社会的意義が高いものといえる。

Research Products

• [Journal Article] HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1a (2020)
  • Author(s): Yoneda A, Minomi K, Tamura Y
  • Journal Title: Oncogene Volume: 39 Issue: 23 Pages: 4519-4537
  • DOI: 10.1038/s41388-020-1311-7
  • Peer Reviewed
• [Journal Article] Heat shock protein 47 maintains cancer cell growth by inhibiting the unfolded protein response transducer IRE1a (2020)
  • Author(s): Akihiro Yoneda, Kaori Sakai-Sawada, Kenjiro Minomi, Yasuaki Tamura
  • Journal Title: Molecular Cancer Research Volume: 18 Issue: 6 Pages: 1-12
  • DOI: 10.1158/1541-7786.mcr-19-0673
  • Peer Reviewed
• [Journal Article] 腫瘍マクロファージによる腫瘍免疫抑制メカニズム (2019)
  • Author(s): 米田明弘
  • Journal Title: 月刊細胞 Volume: 1月号 Pages: 45-47
  • Peer Reviewed
• [Presentation] HSP47 confers chemoresistance on pancreatic cancer cells by suppressing excess release of calcium from the endoplasmic reticulum (2019)
  • Author(s): Akihiro Yoneda, Yasuaki Tamura
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] ヒト膵癌細胞の抗癌剤耐性能におけるHSP47の関与 (2019)
  • Author(s): 米田明弘、田村保明
  • Organizer: 第14回日本臨床ストレス応答学会大会
• [Presentation] HSP47によるヒト膵癌細胞の抗がん剤耐性能獲得機序の解明 (2019)
  • Author(s): 米田明弘、田村保明
  • Organizer: 第42回日本分子生物学会大会
• [Presentation] HSP47 augments a metastatic potential of triple negative breast cancer (2018)
  • Author(s): Akihiro Yoneda, Norio Takei, Kaori Sakai-Sawada, Marina Kosaka, Tasuaki Tamura
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] HSP47によるトリプルネガティブ乳癌の転移能獲得機序の解明 (2018)
  • Author(s): 米田明弘、武井則雄、澤田香織、小坂まりな、田村保明
  • Organizer: 第41回日本分子生物学会