Progression mechanisms of castration-resistant prostate cancer regulated by metabolism of extracellular matrix

• Project/Area Number: 18K09131
• 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: Fujiwara Masaya 三重大学, 医学系研究科, リサーチアソシエイト (10751688)
• Co-Investigator(Kenkyū-buntansha): 杉村 芳樹 三重大学, 医学系研究科, リサーチアソシエイト (90179151) ; 渡邉 昌俊 三重大学, 医学系研究科, 教授 (90273383) ; 石井 健一朗 三重大学, 医学系研究科, リサーチアソシエイト (90397513)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 前立腺癌 / 線維芽細胞 / 三次元的な細胞形態 / 培養基質 / 走化性 / 細胞外マトリックス / ヒドロキシプロリン / スクリーニング法 / 腫瘍内血管 / マトリゲル / 去勢抵抗性前立腺癌 / 癌関連線維芽細胞 / アミノ酸 / スフェロイド

Outline of Final Research Achievements

Prostate cancer (PCa) cells frequently invade the surrounding stroma, leading to heterogenous formation of structural atypia. The surrounding stroma contains multiple functionally diverse populations of fibroblasts that trigger numerous changes in PCa cells including motility. Co-cultures of LNCaP cells with seven of the patient-derived fibroblast lines (PrSC, pcPrF-M5, pcPrF-M7, pcPrF-M23, pcPrF-M24, pcPrF-M28, and pcPrF-M31) formed a thick fibroblast layer that resembled human prostate stromal structures. Four patient-derived fibroblast lines (PrSC, M5, M28, and M31) induced an invasive phenotype in LNCaP cells with a cord-like infiltrating growth pattern. Two patient-derived fibroblast lines (M5 and M28) increased CDH2 mRNA expression in LNCaP cells. These results suggest that the existence of multiple functionally diverse populations of fibroblasts in PCa tissue may be responsible for the diversity in PCa cell invasion, leading to heterogenous formation of structural atypia.

Academic Significance and Societal Importance of the Research Achievements

ホルモン療法下でも前立腺癌細胞を悪性化する線維芽細胞の特徴が同定されれば、病理医によるグリソンスコア分類に加えて、癌間質に含まれる線維芽細胞の特徴が「付加情報」として泌尿器科医へ伝わることにより無駄なホルモン療法を１つでも減らす、すなわち効果が見込める患者にだけホルモン療法を施行する個別化ホルモン療法が実現可能となる。本研究で我々が開発した、培養基質を用いて前立腺癌細胞の三次元的な細胞形態の差異を観察する手法は、activeな線維芽細胞を判別するための新規スクリーニング法の開発へと発展できることが期待された。

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] A Ruptured Blood Blister-Like Aneurysm Associated With Intraperitoneal Hemorrhage Due to Segmental Arterial Mediolysis: A Case Report And Literature Review (2019)
  • Author(s): Tanaka K, Fujiwara M, Okuda Y, Ishida F, Suzuki H
  • Journal Title: World Neurosurgery Volume: 134 Pages: 79-85
  • DOI: 10.1016/j.wneu.2019.10.096
  • Peer Reviewed
• [Journal Article] Rapidly Growthing Mediastinal Cystic Teratoma with Suggestive Perforation by Infection in Pregnancy (2019)
  • Author(s): Tanahashi T, Adachi K, Tarukawa T, Shirakura Y, Fujiwara M
  • Journal Title: Kyobu Geka Volume: 72 Pages: 450-453
  • NAID: 40021931510
  • 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
• [Journal Article] An Unlikely Lesion to Be Identified in the Cervical Esophagus (2018)
  • Author(s): Tanaka Kyosuke、Fujiwara Masaya、Toyoda Hideki
  • Journal Title: Gastroenterology Volume: 155 Issue: 3 Pages: 610-612
  • DOI: 10.1053/j.gastro.2018.01.050
  • Peer Reviewed
• [Journal Article] Predicting the tumorigenic phenotype of human bladder cancer cells by combining with fetal rat mesenchyme (2018)
  • Author(s): Miki Manabu、Ishii Kenichiro、Sasaki Takeshi、Kato Manabu、Kajiwara Shinya、Kanda Hideki、Arima Kiminobu、Hirokawa Yoshifumi、Watanabe Masatoshi、Sugimura Yoshiki
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 36 Issue: 10 Pages: 472-472
  • DOI: 10.1016/j.urolonc.2018.07.008
  • Peer Reviewed
• [Journal Article] Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation (2018)
  • Author(s): Ishii Kenichiro、Sasaki Takeshi、Iguchi Kazuhiro、Kajiwara Shinya、Kato Manabu、Kanda Hideki、Hirokawa Yoshifumi、Arima Kiminobu、Mizokami Atsushi、Sugimura Yoshiki
  • Journal Title: The Prostate Volume: 78 Issue: 11 Pages: 849-856
  • DOI: 10.1002/pros.23643
  • Peer Reviewed
• [Journal Article] Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate (2018)
  • Author(s): Kenichiro Ishii , Sanai Takahashi, Yoshiki Sugimura, Masatoshi Watanabe
  • Journal Title: Journal of Clinical Medicine Volume: 6 Issue: 4 Pages: 68-89
  • DOI: 10.3390/jcm7040068
  • Peer Reviewed / Open Access
• [Journal Article] Additive naftopidil treatment synergizes docetaxel-induced apoptosis in human prostate cancer cells. (2018)
  • Author(s): Ishii K, Matsuoka I, Kajiwara S, Sasaki T, Miki M, Kato M, Kanda H, Arima K, Shiraishi T, Sugimura Y.
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 144 Issue: 1 Pages: 89-98
  • DOI: 10.1007/s00432-017-2536-x
  • Peer Reviewed
• [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
• [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] 血液製剤廃棄率削減の取り組み (2020)
  • Author(s): 河内 亮介、桐山 裕加里、長谷川 雄亮、柴山 貴巳、藤原 雅也
  • Organizer: 第74回 国立病院総合医学会
• [Presentation] 当院における病理診断結果漏れ防止対策について (2020)
  • Author(s): 鈴木 彩華、永田 かおり、柴山 貴巳、藤原 雅也
  • Organizer: 第74回 国立病院総合医学会
• [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
• [Presentation] 当院で経験した類基底細胞型扁平上皮癌16例の臨床的検討 (2019)
  • Author(s): 大岩綾香、坂倉康正、渡邉麻衣子、西村 正、内藤雅大、井端英憲、大本恭裕、渡邉文亮、安達勝利、藤原雅也、藤本 源、小林 哲
  • Organizer: 第60回 日本肺癌学会学術集会
• [Presentation] 短期間で急速な進行を認めた肺癌肉腫の一例 (2019)
  • Author(s): 坂倉康正、大岩綾香、渡邉麻衣子、西村 正、内藤雅大、井端英憲、大本恭裕、藤原雅也、岡野智仁、藤本 源、小林 哲
  • Organizer: 第60回 日本肺癌学会学術集会
• [Presentation] 肺腺癌に対して免疫チェックポイント阻害剤使用後に発生した非細菌性血栓性心内膜炎の1例 (2019)
  • Author(s): 西村 正、大岩綾香、坂倉康正、渡邉麻衣子、内藤雅大、井端英憲、大本恭裕、渡邉文亮、安達勝利、日置巌雄、藤原雅也、藤本 源、小林 哲
  • Organizer: 第60回 日本肺癌学会学術集会
• [Presentation] Loss of fibroblasts-dependent androgen receptor activation in prostate cancer cells develops castration-resistant prostate cancer (2019)
  • Author(s): Kenichiro Ishii, Izumi Matsuoka, Takeshi Sasaki, Manabu Kato, Kohei Nishikawa, Hideki Kanda, Yoshifumi Hirokawa, Kazuhiro Iguchi, Kiminobu Arima, Masatoshi Watanabe, Yoshiki Sugimura
  • Organizer: The American Association for Cancer Research (AACR) Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] 前立腺癌間質の多様性は前立腺癌不均一性にどう影響するのか (2018)
  • Author(s): 石井健一朗、梶原進也、吉川裕美、佐々木 豪、三木 学、加藤 学、神田英輝、有馬公伸、渡邉昌俊、杉村芳樹
  • Organizer: 第106回 日本泌尿器科学会総会
• [Presentation] Fibroblasts preserve androgen receptor signaling in prostate cancer cells under androgen deprivation (2018)
  • Author(s): Kenichiro Ishii, Izumi Matsuoka, Takeshi Sasaki, Shinya Kajiwara, Hideki Kanda, Yoshifumi Hirokawa, Kazuhiro Iguchi, Kiminobu Arima, Masatoshi Watanabe, Yoshiki Sugimura
  • Organizer: 第107回 日本病理学会総会
• [Presentation] Pirfenidone, an anti-fibrotic agent, inhibits cell growth of human cancer cells by induction of G1 cell-cycle arrest (2018)
  • Author(s): Kenichiro Ishii, Eri Usugi, Yoshifumi Hirokawa, Kazuki Kanayama, Chise Matsuda, Katsunori Uchida, Yoshiki Sugimura, Mawatoshi Watanabe
  • Organizer: 第107回 日本病理学会総会
• [Presentation] 前立腺癌微小環境における細胞間相互作用 (2018)
  • Author(s): 石井健一朗、杉村芳樹
  • Organizer: 第5回 前立腺生物学シンポジウム
  • Invited
• [Presentation] 前立腺間質リモデリングは前立腺癌の発生にどう関わるのか (2018)
  • Author(s): 石井健一朗、梶原進也、佐々木 豪、臼杵恵梨、渡邉昌俊、杉村芳樹
  • Organizer: 第33回 発癌病理研究会
• [Presentation] Characterization of human prostate cancer LNCaP sublines differing in androgen-sensitivity: interactions between cancer cells ad fibroblasts (2018)
  • Author(s): Kenichiro Ishii, Shinya Kajiwara, Kazuhiro Iguchi, Manabu Kato, Yoshifumi Hirokawa, Kiminobu Arima, Masatoshi Watanabe, Yoshiki Sugimura
  • Organizer: 第77回 日本癌学会学術総会