Comprehensive analysis of metalloproteinases in cancer-associated fibroblasts

• Project/Area Number: 25860276
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Keio University
• Principal Investigator: Shimoda Masayuki 慶應義塾大学, 医学部, 講師 (70383734)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: がん / 線維芽細胞 / メタロプロテアーゼ

Outline of Final Research Achievements

Carcinoma-associated fibroblasts (CAFs), frequently observed in tumor stroma, are more capable of maintaining cancer stem cells and promoting tumor growth and angiogenesis through their interactions with carcinoma cells. In this study, we performed comprehensive analysis of metalloproteinases in tumor stroma and CAFs. We found that, in stroma associated with human cancer, several metalloproteinases were significantly upregulated, whereas there was a trend towards decreased expression of tissue inhibitors of metalloproteinases (TIMPs). By analyzing CAF microarray datasets, we identified several candidates for CAF-specific metalloproteinases. CAFs also secreted exosomes containing more metalloproteinases including ADAM10 compared to normal adjacent fibroblasts. These data suggest that dysregulation of metalloproteinases in CAFs may contribute to their tumor-propagating ability in patients.

Research Products

• [Journal Article] Tumor suppression by stromal TIMPs (2016)
  • Author(s): Shimoda M, Jackson HW and Khokha R
  • Journal Title: Cellular and Molecular Oncology Volume: － Issue: 3 Pages: e975082-e975082
  • DOI: 10.4161/23723556.2014.975082
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epithelial cell-derived a disintegrin and metalloproteinase-17 confers resistance to colonic inflammation through EGFR activation (2016)
  • Author(s): Shimoda M, Horiuchi K, Sasaki A, Tsukamoto T, Okabayashi K, Hasegawa H, Kitagawa Y and Okada Y
  • Journal Title: EBioMedicine Volume: 5 Pages: 114-24
  • DOI: 10.1016/j.ebiom.2016.02.007
  • Peer Reviewed / Open Access
• [Journal Article] Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. (2014)
  • Author(s): Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, Hess FM, Ohtsuka T, Okada Y, Ailles L, Ludwig A, Wrana JL, Kislinger T and Khokha R
  • Journal Title: Nature Cell Biology Volume: 16 Pages: 889-901
  • Peer Reviewed
• [Journal Article] メタロプロテアーゼによる組織内微小環境因子代謝 (2014)
  • Author(s): 下田将之、岡田保典
  • Journal Title: 病理と臨床 Volume: 32 Pages: 24-30
• [Presentation] 病的組織におけるメタロプロテアーゼの機能解析研究 (2015)
  • Author(s): 下田将之
  • Organizer: 日本病理学会総会
  • Place of Presentation: 名古屋国際会場（愛知県名古屋）
  • Year and Date: 2015-04-30
• [Presentation] 癌間質線維芽細胞形質獲得におけるTIMP分子の機能解析 (2014)
  • Author(s): 下田将之、Rama Khokha
  • Organizer: 第103回病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Book] 実験医学 (2014)
  • Author(s): 下田将之、岡田保典
  • Total Pages: 9
  • Publisher: 羊土社
• [Remarks] 慶應義塾大学医学部 病理学教室
  • URL: http://www.keio-pathology.net/
• [Remarks] 慶應義塾大学医学部 病理学教室
  • URL: http://www.keio-pathology.net/index.html