Development of a novel diagnostic method for prostate cancer that targets tumor promoting fibroblast-derived exosomes

• Project/Area Number: 19K09686
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Mie University
• Principal Investigator: Ishii Kenichiro 三重大学, 医学系研究科, リサーチアソシエイト (90397513)
• Co-Investigator(Kenkyū-buntansha): 佐々木 豪 三重大学, 医学部附属病院, 助教 (20644941) ; 広川 佳史 三重大学, 医学系研究科, 准教授 (30322738) ; 渡邉 昌俊 三重大学, 医学系研究科, 教授 (90273383)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 進行性前立腺がん / アンドロゲン感受性 / がん細胞分化 / がん抑制遺伝子 / NKX3-1 / がん関連線維芽細胞 / エクソソーム / マイクロRNA / 前立腺癌 / 癌関連線維芽細胞 / サブクローン / miRNA / ホルモン療法 / 癌促進性線維芽細胞 / 癌抑制性線維芽細胞 / 癌遺伝子 / 癌抑制遺伝子 / 診断法 / 前立腺がん / がん促進性線維芽細胞

Outline of Research at the Start

進行性前立腺がんに対するホルモン療法を開始する前に、ホルモン療法が効きにくい患者を見分けることができれば、去勢抵抗性前立腺がんへと進展する患者数を確実に減らせる。本研究課題では前立腺がん微小環境を構成する、がん促進性線維芽細胞が分泌するエクソソーム内包マイクロRNAのうち、がん細胞の分化制御に働く機能性分子を同定することで、リキッドバイオプシーによるホルモン療法への反応性や去勢抵抗性前立腺がんへの進展のし易さを予測する血中バイオマーカーとして開発することを目的としている。

Outline of Final Research Achievements

The tumor stroma of prostate cancer (PCa) contains functionally different populations of cancer-associated fibroblasts (CAFs). We hypothesize that cancer progression may be predicted by characterizing the CAFs. We investigated the effects of normal PrSC and 3 PCa patient-derived CAFs on cancer-related gene expressions in 4 human PCa sublines differing in androgen receptor (AR) dependency. The mRNA expression of tumor suppressor gene NKX3-1 in PCa cells having AR dependency was significantly increased by treatment with conditioned medium of PrSC and M5. Microarray profiling of exosomal miRNAs derived from PrSC and M5 identified miR- 449c-3p and miR-3121-3p for miRNAs related to NKX3-1 mRNA. The mRNA expression of NKX3-1 in PCa cells having AR dependency was increased by transfection of miRNA mimic (has-miR-3121-3p). These results suggest that fibroblast-derived miR-3121-3p may be a candidate of stromal morphogen for maintaining PCa cell differentiation in PCa cells having AR dependency.

Academic Significance and Societal Importance of the Research Achievements

進行性前立腺がんに対するホルモン療法を開始する前に、ホルモン療法が有効な患者か、それとも抗がん剤治療を早期に始めるべきか、と判断する指標、例えば血中バイオマーカーがあれば、去勢抵抗性前立腺がんへと進展する患者数を確実に減らせる。我々が提唱する、線維芽細胞の「性質」を指標にすることができれば、ホルモン療法が効きにくく、去勢抵抗性前立腺がんへと進展し易い患者を予測し、早期に適切な治療法を判断・施行できるような前立腺がんの個別化医療実現の一歩となる。

Research Products

• [Journal Article] Heterogeneous induction of an invasive phenotype in prostate cancer cells by co-culturing with patient-derived fibroblasts. (2021)
  • Author(s): Ishii K, Nakagawa Y, Matsuda C, Katoh D, Ichishi M, Shirai T, Hirokawa Y, Fujiwara M, Sugimura Y, Watanabe M.
  • Journal Title: Journal of Cellular Biochemistry Volume: - Issue: 6 Pages: 1-10
  • DOI: 10.1002/jcb.29893
  • Peer Reviewed / Open Access
• [Journal Article] SOX11-induced decrease in vimentin and an increase in prostate cancer cell migration attributed to cofilin activity. (2020)
  • Author(s): Hirokawa YS, Kanayama K, Kagaya M, Shimojo N, Uchida K, Imai H, Ishii K, Watanabe M.
  • Journal Title: Experimental and Molecular Pathology Volume: 117 Pages: 104542-104550
  • DOI: 10.1016/j.yexmp.2020.104542
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands. (2020)
  • Author(s): Mahmud MRA, Ishii K, Lozano CB, Sainz ID, Toi M, Akamatsu S, Fukumoto M, Watanabe M, Takeda S, Ledesma FC, Sasanuma H.
  • Journal Title: Genes to Cells Volume: in press Issue: 7 Pages: 450-465
  • DOI: 10.1111/gtc.12770
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure (2019)
  • Author(s): Kajiwara S, Ishii K, Sasaki T, Kato M, Nishikawa K, Kanda H, Arima K, Watanabe M, Sugimura Y
  • Journal Title: Laboratory Investigation Volume: - Issue: 5 Pages: 670-681
  • DOI: 10.1038/s41374-019-0352-4
  • Peer Reviewed
• [Journal Article] Loss of fibroblast-dependent androgen receptor activation in prostate cancer cells is involved in the mechanism of acquired resistance to castration (2019)
  • Author(s): Ishii K, Matsuoka I, Sasaki T, Nishikawa K, Kanda H, Imai H, Hirokawa Y, Iguchi K, Arima K, Sugimura Y
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 9 Pages: 1379-1379
  • DOI: 10.3390/jcm8091379
  • Peer Reviewed / Open Access
• [Journal Article] Pirfenidone, an Anti-Fibrotic Drug, Suppresses the Growth of Human Prostate Cancer Cells by Inducing G1 Cell Cycle Arrest (2019)
  • Author(s): Ishii Kenichiro、Sasaki Takeshi、Iguchi Kazuhiro、Kato Manabu、Kanda Hideki、Hirokawa Yoshifumi、Arima Kiminobu、Watanabe Masatoshi、Sugimura Yoshiki
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 1 Pages: 44-44
  • DOI: 10.3390/jcm8010044
  • Peer Reviewed / Open Access
• [Journal Article] Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest (2019)
  • Author(s): Usugi Eri、Ishii Kenichiro、Hirokawa Yoshifumi、Kanayama Kazuki、Matsuda Chise、Uchida Katsunori、Shiraishi Taizo、Watanabe Masatoshi
  • Journal Title: Pharmacology Volume: 103 Issue: 5-6 Pages: 250-256
  • DOI: 10.1159/000496831
  • Peer Reviewed
• [Journal Article] Tyrosine kinase inhibitor therapy prescribed for non-urologic diseases can modify PSA titers in urology patients (2018)
  • Author(s): Sasaki Takeshi、Franco Omar E.、Ohishi Kohshi、Filipovich Yana、Ishii Kenichiro、Crawford Susan E.、Takahashi Naoto、Katayama Naoyuki、Sugimura Yoshiki、Hayward Simon W.
  • Journal Title: The Prostate Volume: 79 Issue: 3 Pages: 259-264
  • DOI: 10.1002/pros.23730
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Prostate cancer subclones partially lose progressive communications with patient-derived fibroblasts (2021)
  • Author(s): Kenichiro Ishii, Yasuhisa Nakagawa, Chise Matsuda, Masako Ichishi, Taku Shirai, Yoshifumi Hirokawa, Masaya Fujiwara, Kazuhiro Iguchi, Yoshiki Sugimura, Masatoshi Watanabe
  • Organizer: 第110回 日本病理学会総会
• [Presentation] Heterogeneous induction of prostate cancer invasive phenotype by patient-derived fibroblasts (2021)
  • Author(s): Yasuhisa Nakagawa, Kenichiro Ishii, Chise Matsuda, Daisuke Kato, Masako Ichishi, Taku Shirai, Yoshifumi Hirokawa, Masaya Fujiwara, Yoshiki Sugimura, Masatoshi Watanabe
  • Organizer: 第110回 日本病理学会総会
• [Presentation] 癌関連線維芽細胞の多様性と前立腺癌細胞における癌抑制遺伝子発現の関係 (2021)
  • Author(s): 松田 知世、石井 健一朗、中川 泰久、白井 拓、佐々木 豪、広川 佳史、井口 和弘、渡邉 昌俊
  • Organizer: 第110回 日本病理学会総会
• [Presentation] Progressive prostate cancer LNCaP subclones partially retain regressive communications with patient-derived fibroblasts (2021)
  • Author(s): Kenichiro Ishii, Chise Matsuda, Yasuhisa Nakagawa, Taku Shirai, Yoshifumi Hirokawa, Takeshi Sasaki, Kazuhiro Iguchi, Masatoshi Watanabe
  • Organizer: AACR Annual Meeting 2021
• [Presentation] Cancer-restraining CAFs produce soluble factors targeting upregulation of NKX3-1 in prostate cancer cells (2021)
  • Author(s): Chise Matsuda, Kenichiro Ishii, Yasuhisa Nakagawa, Taku Shirai, Yoshifumi Hirokawa, Kazuki Kanayama, Kazuhiro Iguchi, Masatoshi Watanabe
  • Organizer: 第80回 日本癌学会学術総会
• [Presentation] 線維芽細胞の老化は前立腺癌関連線維芽細胞様分化の獲得なのか？ (2020)
  • Author(s): 中川 泰久、石井 健一朗、藤原 雅也、一志 真子、加藤 大祐、松田 知世、白井 拓、広川 佳史、杉村 芳樹、渡邉 昌俊
  • Organizer: 第109回 日本病理学会総会
• [Presentation] 線維芽細胞による前立腺癌細胞の揺らぎとアンドロゲン感受性の関係 (2020)
  • Author(s): 松田 知世、石井 健一朗、中川 泰久、白井 拓、佐々木 豪、広川 佳史、井口 和弘、渡邉 昌俊
  • Organizer: 第109回 日本病理学会総会
• [Presentation] 一次線毛動態を指標にした前立腺癌細胞に反応する線維芽細胞の同定 (2020)
  • Author(s): 白井 拓、石井 健一朗、中川 泰久、藤原 雅也、一志 真子、松田 知世、広川 佳史、杉村 芳樹、稲垣 昌樹、渡邉 昌俊
  • Organizer: 第109回 日本病理学会総会
• [Presentation] Direct contact of heterogeneous fibroblasts with cancer cells regulates the invasive phenotype of prostate cancer cells (2020)
  • Author(s): Kenichiro Ishii, Yasuhisa Nakagawa, Taku Shirai, Masako Ichishi, Masaya Fujiwara, Daisuke Kato, Chise Matsuda, Yoshifumi Hirokawa, Yoshiki Sugimura, Masaki Inagaki, Masatoshi Watanabe
  • Organizer: AACR Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] Heterogenous induction of cadherin switching in prostate cancer cells by co-culturing with activated fibroblasts (2020)
  • Author(s): Yasuhisa Nakagawa, Kenichiro Ishii, Chise Matsuda, Masaya Fujiwara, Daisuke Kato, Taku Shirai, Yoshifumi Hirokawa, Yoshiki Sugimura, Masatoshi Watanabe
  • Organizer: 第79回 日本癌学会学術総会
• [Presentation] Tumor suppressor gene expression in prostate cancer cells is altered by fibroblasts in a cell-specific manner (2020)
  • Author(s): Chise Matsuda, Kenichiro Ishii, Yasuhisa Nakagawa, Taku Shirai, Yoshifumi Hirokawa, Kazuhiro Iguchi, Masatoshi Watanabe
  • Organizer: 第79回 日本癌学会学術総会
• [Presentation] Primary cilia dynamics in fibroblasts visualize the response to prostate cancer cells (2020)
  • Author(s): Taku Shirai, Kenichiro Ishii, Yasuhisa Nakagawa, Daisuke Kato, Masaya Fujiwara, Chise Matsuda, Yoshifumi Hirokawa, Yoshiki Sugimura, Masaki Inagaki, Masatoshi Watanabe
  • Organizer: 第79回 日本癌学会学術総会
• [Presentation] 前立腺癌微小環境を標的にした抗線維化薬ピルフェニドンの新規薬理効果 (2019)
  • Author(s): 石井健一朗、吉川裕美、松岡いづみ、佐々木 豪、加藤 学、西川晃平、神田英輝、有馬公伸、渡邉昌俊、杉村芳樹
  • Organizer: 第107回 日本泌尿器科学会総会
• [Presentation] 前立腺癌進展において癌－間質相互作用に非依存的な増殖機構の解析 (2019)
  • Author(s): 松岡いづみ、石井健一朗、佐々木 豪、梶原進也、加藤 学、西川晃平、神田英輝、有馬公伸、渡邉昌俊、杉村芳樹
  • Organizer: 第107回 日本泌尿器科学会総会
• [Presentation] チロシンキナーゼ阻害剤、ニロチニブによる前立腺癌細胞に対するオフターゲット効果 (2019)
  • Author(s): 佐々木 豪、大石晃嗣、石井健一朗、高橋直人、片山直之、杉村芳樹
  • Organizer: 第107回 日本泌尿器科学会総会
• [Presentation] 上皮－間質組み替えモデルおよび器官培養法を用いた泌尿器疾患研究の利点と欠点 (2019)
  • Author(s): 加藤 学、佐々木 豪、石井健一朗、杉村芳樹
  • Organizer: 第107回 日本泌尿器科学会総会
  • Invited
• [Presentation] Pirfenidone, an anti-fibrotic drug, suppresses the growth of human cancer cells by inducing G1 cell cycle arrest (2019)
  • Author(s): Kenichiro Ishii, Eri Usugi, Yasuhisa Nakagawa, Chise Matsuda, Masako Ichishi, Masaya Fujiwara, Katsunori Uchida, Yoshifumi Hirokawa, Yoshiki Sugimura, Masatoshi Watanabe
  • Organizer: 第108回 日本病理学会総会
• [Presentation] 前立腺癌微小環境を模した線維芽細胞の新規スクリーニング法の開発 (2019)
  • Author(s): 中川泰久、石井健一朗、藤原雅也、松田知世、一志真子、内田克典、広川佳史、杉村芳樹、渡邉昌俊
  • Organizer: 第108回 日本病理学会総会
• [Presentation] Sonic hedgehog-improved prostate stromal structure in the castrated mouse does not suppress the proliferation of basal epithelial cells (2019)
  • Author(s): Kenichiro Ishii, Manabu Kato, Masatoshi Watanabe, Yoshiki Sugimura
  • Organizer: 第78回 日本癌学会学術総会
• [Presentation] Effects of fibroblasts on the three-dimensional morphogenesis of human prostate cancer cells on a viscous substrate (2019)
  • Author(s): Yasuhisa Nakagawa, Kenichiro Ishii, Masaya Fujiwara, Yoshifumi Hirokawa, Yoshiki Sugimura, Masatoshi Watanabe
  • Organizer: 第78回 日本癌学会学術総会