Development of a novel therapy normalizing tumor-associated stroma

• Project/Area Number: 15K14385
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Juntendo University
• Principal Investigator: Akira Orimo 順天堂大学, 医学(系)研究科(研究院), 准教授 (70275866)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); 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: 癌微小環境 / ＣＡＦｓ / エピゲノム変異 / 乳癌 / ヒストン脱アセチル化酵素阻害剤 / ＣＡＦs / 癌進展 / 癌内線維芽細胞 / HDAC inhibitor

Outline of Final Research Achievements

CAFs（Carcinoma-associated fibroblasts）are often present in various human carcinomas. These fibroblasts are also composed of myofibroblasts, a hallmark of activated fibroblasts and known to promote tumor progression. However, molecular targets on CAFs have not been elucidated yet. In this study, we claim that HDAC inhibitors are a promising to inactivate tumor-promoting CAFs to prevent tumor progression.

Research Products

• [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
• [Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling. (2018)
  • Author(s): Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
  • Journal Title: Oncogene. Volume: 37 Issue: 9 Pages: 1205-1219
  • DOI: 10.1038/s41388-017-0033-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer. (2016)
  • Author(s): Escudero-Esparza A., Bartoschek M., Gialeli C., Okroj M., Owen S., Jirström K., Orimo A., Jiang WG., Pietras K., Blom AM.
  • Journal Title: Oncotarget Volume: 7, Issue: 47 Pages: 76920-76933
  • DOI: 10.18632/oncotarget.12729
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. (2016)
  • Author(s): Mezawa, Y. and Orimo A
  • Journal Title: Cell and tissue research Volume: 365 Issue: 3 Pages: 675-89
  • DOI: 10.1007/s00441-016-2471-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer. (2016)
  • Author(s): 2.Englund E, Bartoschek M, Reitsma B, Jacobsson L, Escudero-Esparza A, Orimo A, Leandersson K, Hagerling C, Aspberg A, Storm P, Okroj M, Mulder H, Jirström K, Pietras K, Blom AM.
  • Journal Title: Oncogene. Volume: １１ Issue: 43 Pages: 5585-5596
  • DOI: 10.1038/onc.2016.98
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer. (2016)
  • Author(s): Englund E, Bartoschek M, Reitsma B, Jacobsson L, Escudero-Esparza A, Orimo A, Leandersson K, Hagerling C, Aspberg A, Storm P, Okroj M, Mulder H, Jirström K, Pietras K, Blom AM.
  • Journal Title: Oncogene Volume: 11 Pages: 10-10
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The human complement inhibitor Sushi Domain-Containing Protein 4 (SUSD4) expression in tumor cells and CD8+ T cells is associated with better prognosis of breast cancer patients. (2015)
  • Author(s): Englund E, Reitsma B, King BC, Escudero-Esparza A, Owen S, Orimo A, Okroj M, Anagnostaki L, Jiang WG, Jirström K, Blom AM.
  • Journal Title: BMC Cancer, Volume: 19 Pages: 737-737
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 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
  • Invited
• [Presentation] 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
  • Invited
• [Presentation] Carcinoma-associated fibroblasts upregulate endoglin expression to mediate their activated myofibroblastic traits. (2017)
  • Author(s): Shoki Okubo, Yoshihiro Mezawa, Yasuhiko Ito, Sumio Watanabe, Okio Hino, and Akira Orimo
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Carcinoma-associated fibroblasts attenuate CD26/dipeptidyl peptidase-4 expression via activation of the TGF-β-Smad2/3 pathway. (2017)
  • Author(s): Yoshihiro Mezawa, Chikao Morimoto, Okio Hino, and Akira Orimo
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Carcinoma-associated fibroblasts promote metastatic seeding of the highly epithelial human breast carcinoma cell cluster with a quasi-mesenchymal trait. (2017)
  • Author(s): Yasuhiko Ito, Yuko Matsumura, Yoshihiro Mezawa, Kaidiliavi Sulidan, Nadila Wali, Yasuhiko Terao, Satoru Takeda, Ko Okumura, Kazuyoshi Takeda, Okio Hino, Akira Orimo
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] CAFs boost mammary cancer invasion and metastasis via formation of the epithelial and mesenchymal tumor cell cluster. (2017)
  • Author(s): Akira Orimo, Yasuhiko Ito, Yoshihiro Mezawa, Kaidiliavi Sulidan, Nadila Wali1, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Yuko Matsumura
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] CAFs boost mammary cancer metastasis via increasing the cell-cell adhesion (2016)
  • Author(s): Akira Orimo, Nadila Wali, Yasuhiko Ito, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Yuko Matsumura
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] CD26/dipeptidyl peptidase-4 expression is downregulated in carcinoma-associated fibroblasts via activation of TGF-β signaling (2016)
  • Author(s): Yoshihiro Mezawa1), Chikao Morimoto2), Okio Hino1), and Akira Orimo1
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Dissecting molecular mechanisms underlying CAF-induced metastatic dissemination of human breast carcinomas. (2016)
  • Author(s): Nadila Wali, Yuko Matsumura, Yasuhiko Ito, Kaoru Mogushi, Yasuhisa Terao, Satoru Takeda, Ko Okumura, Kazuyoshi Takeda, Okio Hino, and Akira Orimo
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Carcinoma-associated fibroblasts confer adherent epithelial cell traits in breast cancer cells to promote metastasis (2015)
  • Author(s): Orimo A
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] 癌細胞と癌内線維芽細胞の共進化および癌悪性化 (2015)
  • Author(s): Orimo A
  • Organizer: 第30回発癌病理研究会
  • Place of Presentation: 小豆島
  • Year and Date: 2015-08-27
  • Invited
• [Presentation] 肺線維症研究の最前線 線維化と癌悪性化 (2015)
  • Author(s): 折茂彰
  • Organizer: 第12回肺研究フォーラム21
  • Place of Presentation: 東京
  • Year and Date: 2015-04-18
  • Invited
• [Book] 実験医学 (2016)
  • Author(s): 折茂彰
  • Total Pages: 141
  • Publisher: 羊土社
• [Book] 呼吸 (2016)
  • Author(s): 伊藤匠、松村優子、伊藤恭彦、折茂彰
  • Total Pages: 94
  • Publisher: 呼吸研究
• [Book] 実験医学 (2015)
  • Author(s): 折茂彰, 松村優子,本多一貴, Nadila Wali,
  • Total Pages: 210
  • Publisher: 羊土社
• [Book] 呼吸器内科 (2015)
  • Author(s): 折茂彰, 松村優子，伊藤恭彦，十合晋作
  • Total Pages: 87
  • Publisher: 科学評論社
• [Book] 肺の損傷と発癌機序「Annual Review呼吸器2015 (2015)
  • Author(s): 谷口源太郎、折茂彰
  • Total Pages: 258
  • Publisher: 中外医学社
• [Remarks] がん転移を促進するがん間質のしくみを探る
  • URL: http://ganshien.umin.jp/research/main/orimo/index.html
• [Remarks] 文部科学省科学研究費新学術領域―がん研究分野の特性等を踏まえた支援活動
  • URL: http://ganshien.umin.jp/research/main/orimo/index.html