Identification of biomarkers for tumor-promoting CAFs

• Project/Area Number: 18K07207
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Juntendo University
• Principal Investigator: Orimo Akira 順天堂大学, 医学(系)研究科(研究院), 教授 (70275866)
• Co-Investigator(Kenkyū-buntansha): ワリ ナディラ 順天堂大学, 医学(系)研究科(研究院), 非常勤助教 (90751868)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CAFs / TGF-b / Endoglin / 癌促進 / 乳癌 / 癌浸潤・転移 / CAFｓ / TGF-bシグナル / 癌微小環境 / endogln / TGF-ｂシグナル / 癌内線維芽細胞 / endoglin (CD105)

Outline of Final Research Achievements

Applicants found that cancer-associated fibroblasts (CAFs), which are abundant in the cancer microenvironment, act on nearby breast cancer cells to promote cancer malignant transformation. It has been shown that activation of stromal cell-derived factor 1 (SDF-1) and TGF-β autocrine signal is important for maintaining the phenotype of cancer-promoting CAFs. In addition, the applicants recently found that TGF-β receptor-binding protein endoglin (CD105) is highly expressed in breast cancer-derived CAFs by DNA microarray analysis. In this study, it was clarified that endoglin, which is the co-receptor of TGF-β, is highly expressed on CAFs, activates the TGF-β-Smad2/3 signal, and maintains myofibroblastic and cancer-promoting abilities. Furthermore, it was clarified that the expression of endoglin in CAFs is useful as a biomarker for predicting the prognosis of CAFs.

Academic Significance and Societal Importance of the Research Achievements

申請者らは、独自に樹立した乳癌由来CAFsを使用し、対照的に非癌部より抽出された線維芽細胞との比較により、CAFsで遺伝子発現が変化している独自の遺伝子群を同定し、本研究では、endoglinに焦点を当て、CAFsでTGF-bやSDF-1オートクラインシグナルとの関与を明らかにした。また、本研究ではCAFsにおけるendoglinの発現が、患者の予後予測マーカ―になることを明確にした。さらに、CAFsにおけるendoglinの発現抑制を基に、CAFsを標的にした新規癌治療法の開発に今後役立つ可能性を見出した。

Research Products

• [Journal Article] Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy (2020)
  • Author(s): Okabe Takahiro、Togo Shinsaku、Fujimoto Yuichi、Watanabe Junko、Sumiyoshi Issei、Orimo Akira、Takahashi Kazuhisa
  • Journal Title: Cancers Volume: 12 Issue: 12 Pages: 3588-3588
  • DOI: 10.3390/cancers12123588
  • Peer Reviewed / Open Access
• [Journal Article] Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. (2019)
  • Author(s): Mizukoshi K, Okazawa Y, Haeno H, Koyama Y, Sulidan K, Komiyama H, Saeki H, Ohtsuji N, Ito Y, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: Int J Cancer Volume: 146 Issue: 9 Pages: 2547-2562
  • DOI: 10.1002/ijc.32672
  • Peer Reviewed / Open Access
• [Journal Article] Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity. (2019)
  • Author(s): Matsumura Y, Ito Y, Mezawa Y, Sulidan K, Daigo Y, Hiraga T, Mogushi K, Wali N, Suzuki H, Itoh T, Miyagi Y, Yokose T, Shimizu S, Takano A, Terao Y, Saeki H, Ozawa M, Abe M, Takeda S, Okumura K, Habu S, Hino O, Takeda K, Hamada M, Orimo A.
  • Journal Title: Life Sci Alliance Volume: 2(4):e201900425. Issue: 4 Pages: 1-24
  • DOI: 10.26508/lsa.201900425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD26 expression is attenuated by TGF-β and SDF-1 autocrine signaling on stromal myofibroblasts in human breast cancers (2019)
  • Author(s): Mezawa Y, Daigo Y, Takano A, Miyagi Y, Yokose T, Yamashita T, Morimoto T, Hino O, Orimo A.
  • Journal Title: Cancer Med Volume: 8 Issue: 8 Pages: 3936-3948
  • DOI: 10.1002/cam4.2249
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD26 expression is attenuated by TGF-β and SDF-1 autocrine signaling on stromal myofibroblasts in human breast cancers (2019)
  • Author(s): Yoshihiro Mezawa, Yataro Daigo, Atsushi Takano, Yohei Miyagi, Tomoyuki Yokose, Toshinari Yamashita, Chikao Morimoto, Okio Hino, and Akira Orimo
  • Journal Title: Cancer Medicine, 印刷中 Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] High-sensitivity detection of micrometastases generated by GFP lentivirus-transduced organoids cultured from a patient-derived colon tumor. (2018)
  • Author(s): OkazawaY, Mizukoshi K, KoyamaY, Okubo S, Komiyama H, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: J Vis Exp Volume: 136(e57374) Issue: 136 Pages: 463-473
  • DOI: 10.3791/57374
  • Peer Reviewed / Open Access
• [Journal Article] Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. (2018)
  • Author(s): Roswall P, Bocci M, Bartoschek M, Li H, Kristiansen G, Jansson S, Lehn S, Sjölund J, Reid S, Larsson C, Eriksson P, Anderberg C, Cortez E, Saal LH, Orsmark-Pietras C, Cordero E, Haller BK, Häkkinen J, Burvenich IJG, Lim E, Orimo A, Höglund M, Rydén L, Moch H, Scott AM, Eriksson U, Pietras K.
  • Journal Title: Nat Med Volume: 24(4) Issue: 4 Pages: 463-473
  • DOI: 10.1038/nm.4494
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 癌内線維芽細胞によるヒト乳癌細胞の浸潤・転移促進機構 (2020)
  • Author(s): 折茂 彰
  • Organizer: ２０１９年度先端モデルプラットホーム成果発表会 成果発表ワークショップ 分子プロファイリング支援班
  • Invited
• [Presentation] ITGA11-fibronectinカスケードを介する癌関連肺線維芽細胞の遊走能の解明 (2019)
  • Author(s): 岩井萌、十合晋作、川路英也、伊藤昌可、Miniwan Tulafu、渡邊純子、門屋講太郎、難波由喜子、鈴木健司、折茂 彰、吉田浩二、河合純、林崎良英、高橋和久
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] 患者大腸癌細胞集団の中間型上皮間葉移行を介した浸潤・転移機構 (2019)
  • Author(s): 水越幸輔、岡澤 裕、波江野洋、小山 侑、大久保捷奇、Kaidiliavi Sulidan、 伊藤恭彦、小見山、光、杉本起一、小島 豊、五藤倫敏、垣生園子、樋野興夫、 折茂 彰、坂本一博
  • Organizer: 第30回 日本消化器癌発生学会総会
• [Presentation] Forkhead box protein O1 mediates the activated myofibroblastic state in carcinoma-associated fibroblasts. (2019)
  • Author(s): Takumi Koyama, Yoshihiro Mezawa, Yu Koyama, Yasuhiko Ito, Keisuke Sugahara, Okio Hino, Akira Katakura, and Akira Orimo
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 癌内線維芽細胞による癌細胞の浸潤・転移促進機構 (2019)
  • Author(s): 折茂彰
  • Organizer: 東京歯科大学大学院セミナー
• [Presentation] RUNX3 expression mediates cross-talk between TGF-β and SDF-1 signaling and WNT-β-catenin signaling in human breast CAFs. (2019)
  • Author(s): Yu Koyama, Go Yoshida, Yasuhiko Ito, Yoshihiro Mezawa, Takumi Koyama, Keisuke Sugahara, Akira Katakura, and Akira Orimo
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] CAF-induced partial epithelial-mesenchymal transition mediates formation of metastatic human breast tumor cell clusters. (2019)
  • Author(s): Akira Orimo, Yasuhiko Ito, Yoshihiro Mezawa, Kaidiliavi Sulidan, Yataro Daigo, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Yuko Matsumura
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 中間型上皮間葉移行による患者大腸癌細胞クラスターの転移への寄与 (2018)
  • Author(s): 岡澤 裕、水越 幸輔、小山 侑、大久保 捷奇、Kaidiliavi Sulidan、伊藤 恭彦、小見山 博光、小島 豊、五藤 倫敏、垣生 園子、樋野 興夫、折茂 彰、坂本 一博
  • Organizer: 第29回 日本消化器癌発生学会総会 東京
• [Presentation] 癌内線維芽細胞と上皮間葉移行の可塑性 (2018)
  • Author(s): 折茂彰
  • Organizer: 第16回がんとハイポキシア研究会 千葉
  • Invited
• [Presentation] シンポジウム 炎症と発癌 CAFs induce formation of metastatic human breast tumor cell clusters with partial epithelial-mesenchymal transition (2018)
  • Author(s): Akira Orimo, Yasuhiko Ito, Yoshihiro Mezawa, Kaidiliavi Sulidan, Yataro Daigo, Nadila Wali, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Yuko Matsumura
  • Organizer: 第77回日本癌学会学術総会 大阪
  • Invited
• [Presentation] Activation of Src signaling mediates carcinoma-associated fibroblast-promoted metastasis in human breast cancers. (2018)
  • Author(s): Yasuhiko Ito, Yuko Matsumura, Yoshihiro Mezawa, Kaidiliavi Sulidan, Nadila Wali, Yasuhisa Terao, Satoru Takeda, Ko Okumura, Kazuyoshi Takeda, Okio Hino, Akira Orimo
  • Organizer: 第77回日本癌学会学術総会 大阪
• [Presentation] RUNX3 expression mediates TGF-β and SDF-1 autocrine signaling in human breast CAF myofibroblasts. (2018)
  • Author(s): Yu Koyama, Shiori Sakayori, Yasuhiko Ito, Yoshihiro Mezawa, Takumi Koyama, Keisuke Sugahara, Okio Hino, Akira Katakura, and Akira Orimo
  • Organizer: 第77回日本癌学会学術総会 大阪
• [Presentation] Endoglin expression mediates myofibroblastic and tumor-promoting carcinoma-associated fibroblasts in human breast carcinomas. (2018)
  • Author(s): Shoki Okubo, Yoshihiro Mezawa, Yasuhiko Ito, Okio Hino, and Akira Orimo
  • Organizer: 第77回日本癌学会学術総会 大阪
• [Presentation] Histone deacetylase mediates myofibroblastic and tumor-promoting phenotypes in human breast carcinoma-associated fibroblasts via TGF-β autocrine signaling. (2018)
  • Author(s): Yoshihiro Mezawa, Okio Hino, Seimiya Hiroyuki and Akira Orimo
  • Organizer: 第77回日本癌学会学術総会 大阪
• [Presentation] 癌関連線維芽細胞が示す癌促進能と筋線維芽細胞様の特性を維持するエピゲノム変化の探索 (2018)
  • Author(s): 目澤 義弘、樋野 興夫、折茂 彰
  • Organizer: 第27回日本癌病態治療研究会 千葉
• [Presentation] ワークショップ 乳癌内線維芽細胞と癌浸潤・転移 (2018)
  • Author(s): 折茂 彰、伊藤 恭彦、目澤 義弘、Kaidiliavi Sulidan、Nadila Wali、竹田 省、奥村 康、竹田 和由、樋野 興夫、浜田 道昭、松村 優子
  • Organizer: 第27回日本癌病態治療研究会 千葉
• [Presentation] 招待講演：癌内線維芽細胞が及ぼす癌浸潤・転移機構 (2018)
  • Author(s): 折茂彰
  • Organizer: 国立がんセンター中央病院 東京
  • Invited
• [Presentation] 招待講演：癌内線維芽細胞と癌悪性化 (2018)
  • Author(s): 折茂彰
  • Organizer: 第836回千葉県がんセンター研究所集談会 千葉
  • Invited
• [Presentation] 招待講演：癌内線維芽細胞の癌悪性化機構の解明および治療標的としての展望 (2018)
  • Author(s): 折茂彰
  • Organizer: 公益財団法人微生物化学研究会セミナー 東京
  • Invited
• [Book] レンチウイルスベクターDNAの安定的な回収法、実験医学 (2019)
  • Author(s): 伊藤恭彦、目澤義弘、小山侑、折茂彰
  • Total Pages: 6
  • Publisher: 1月号、2019年羊土社
• [Remarks] 折茂彰 研究グループ
  • URL: https://a-orimo.wixsite.com/mysite
• [Remarks] research map
  • URL: https://researchmap.jp/Akira_Orimo/