Role of tumor-associated macrophages in the acquisition of cancer cell stemness and its application for anti-tumor therapy

• Project/Area Number: 15K18435
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• 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): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腫瘍マクロファージ / 癌幹細胞 / 幹細胞様特性 / 抗癌剤耐性

Outline of Final Research Achievements

Chemoresistance of cancer cells is a leading cause of chemotherapy and molecular target therapy against tumors. The purpose of the present study was to clarify the mechanism by which tumor-associated macrophages (TAMs) induce the acquisition of cancer cell stemness and promote the tumorigenic potential of cancer cells. Here we showed that IL-6 and HB-EGF derived from TAMs induce acquisition of cancer cell stemness and enhance the tumorigenicity of cancer cells. The tumorigenicity of cancer cells in mice that have IL-6-depleted or HB-EGF-depleted macrophages was significantly lower than that in wild-type mice. These results indicated that both IL-6 and HB-EGF derived from TAMs play a crucial role in cancer cell stemness and augment of tumorigenic potential of cancer cells, and suggested that targeted depletion of both IL-6 and HB-EGF may become a therapeutic modality for tumors.

Research Products

• [Journal Article] Endoplasmic reticulum oxidase 1α is critical for collagen secretion from and membrane type 1-matrix metalloproteinase levels in hepatic stellate cells (2017)
  • Author(s): Fujii M, Yoneda A, Takei N, Sakai-Sawada K, Kosaka M, Minomi K, Yokoyama A, Tamura Y.
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 38 Pages: 15649-15660
  • DOI: 10.1074/jbc.m117.783126
  • NAID: 120006522663
  • Peer Reviewed
• [Journal Article] 腫瘍マクロファージによる腫瘍細胞の幹細胞様特性獲得機序とその応用 (2017)
  • Author(s): 米田明弘、武井則雄、澤田香織、田村保明
  • Journal Title: 月刊 細胞 Volume: 49 Pages: 35-38
• [Presentation] HSP47 maintains cancer cell proliferation via its inhibitory effect on ER stress sensor IRE1α activity (2017)
  • Author(s): Yoneda A, Takei N, Sawada K, Kosaka M, Minomi K, Tamura Y
  • Organizer: 第76回日本癌学会学術集会
• [Presentation] 癌細胞におけるHSP47のERストレスセンサーIRE1aの活性調節機構 (2017)
  • Author(s): 米田明弘、武井則雄、澤田香織、小坂まりな、味呑憲二郎、田村保明
  • Organizer: 第40回日本分子生物学会