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Treatment approach through clarification of the mechanisms of immune cell- cytokine network in prostate cancer

Research Project

Project/Area Number 19K09689
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56030:Urology-related
Research InstitutionOsaka University

Principal Investigator

Nonomura Norio  大阪大学, 医学系研究科, 教授 (30263263)

Co-Investigator(Kenkyū-buntansha) 松下 慎  大阪大学, 医学部附属病院, 医員 (40824785)
藤田 和利  近畿大学, 医学部, 准教授 (50636181)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords前立腺癌 / 発癌 / 高脂肪食 / サイトカイン / 炎症 / 腸内細菌叢 / 短鎖脂肪酸 / 免疫細胞 / 肥満 / メトフォルミン / ケモカイン
Outline of Research at the Start

前立腺癌の発症・進展には全身性および局所の炎症が重要な役割 を果たしている可能性がある。本研究では以下について研究を行う。
1. 前立腺癌モデルマウス(前立腺特異的 P t e n ノックアウトマウス)を用いて、前立腺癌 の発症・増殖・進展と慢性炎症との関連を免疫細胞―サイトカイン・ケモカイン―腫 瘍細胞の免疫ネットワークに着目し検討する。
2. 免疫ネットワークを阻害することによる前立腺癌発症・進展への影響を遺伝子レベル で解析する。マウスで得られた知見を、ヒトの臨床検体を用いて検討し、前立腺癌の 新規発症予防および治療法の開発を目指す。

Outline of Final Research Achievements

The possibility of induction and development of prostate cancer by cytokines was analyzed by using prostate-specific PTEN knockout mouse model. In the prostate of this model mouse, innate immune cells such as mast cells and macrophages are infiltrated causing inflammation. The expression of IL6 was increased in the prostate leading to STAT3 phosphorylation. Administration of anti-IL& receptor antibody blocked the activation of this signal transduction and suppressed prostate carcinogenesis. High fat diet promoted prostate carcinogenesis in this model compared to normal diet. We have identified specific gut microbiome which produces short chain fatty acid (SCFA) as one of the metabolites. SCFA promote IGF1 production possibly in the liver.

Academic Significance and Societal Importance of the Research Achievements

食生活の欧米化に伴って、前立腺癌は日本人男性で最も罹患率の高い癌となった。本研究により、前立腺の発癌には、局所における炎症とIL6のシグナル伝達経路の活性化が重要であること、高脂肪食が腸内細菌叢の変化を来たし、短鎖脂肪酸(SCFA)の増加とそれに伴うIGF1の産生増加が関わっていることが明らかとなった。このことは、前立腺癌の発生を直接的に局所の炎症を抑制すること、或いは腸内細菌叢へ修飾を加えることで抑制できる可能性を示唆していて、学術的重要性が高い。食生活への介入による腸内細菌叢の変化を介した、前立腺発癌予防の可能性は、超高齢化社会を迎えた我が国において非常に大きな社会的意義を持つ。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (29 results)

All 2022 2021 2020 2019 2018

All Journal Article (14 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 14 results,  Open Access: 10 results) Presentation (14 results) (of which Invited: 2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Firmicutes in Gut Microbiota Correlate with Blood Testosterone Levels in Elderly Men.2022

    • Author(s)
      Matsushita M, Fujita K, Motooka D, Hatano K, Hata J, Nishimoto M, Banno E, Takezawa K, Fukuhara S, Kiuchi H, Pan Y, Takao T, Tsujimura A, Yachida S, Nakamura S, Obara W, Uemura H, Nonomura N.
    • Journal Title

      World J Mens Health

      Volume: in press Issue: 3 Pages: 517-525

    • DOI

      10.5534/wjmh.210190

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High-fat diet promotes prostate cancer growth through histamine signaling.2022

    • Author(s)
      Matsushita M, Fujita K, Hatano K, Hayashi T, Kayama H, Motooka D, Hase H, Yamamoto A, Uemura T, Yamamichi G, Tomiyama E, Koh Y, Kato T, Kawashima A, Uemura M, Nojima S, Imamura R, Mubeen A, Netto GJ, Tsujikawa K, Nakamura S, Takeda K, Morii E, Nonomura N.
    • Journal Title

      Int J Cancer

      Volume: in press Issue: 4 Pages: 623-636

    • DOI

      10.1002/ijc.34028

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.2021

    • Author(s)
      Matsushita M, Fujita K, Hayashi T, Kayama H, Motooka D, Hase H, Jingushi K, Yamamichi G, Yumiba S, Tomiyama E, Koh Y, Hayashi Y, Nakano K, Wang C, Ishizuya Y, Kato T, Hatano K, Kawashima A, Ujike T, Uemura M, Imamura R, Rodriguez Pena MDC, Gordetsky JB, Netto GJ, Tsujikawa K, Nakamura S, Takeda K, Nonomura N.
    • Journal Title

      Cancer Research

      Volume: 81 Issue: 15 Pages: 4014-4026

    • DOI

      10.1158/0008-5472.can-20-4090

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The gut microbiota associated with high-Gleason prostate cancer.2021

    • Author(s)
      Matsushita M, Fujita K, Motooka D, Hatano K, Fukae S, Kawamura N, Tomiyama E, Hayashi Y, Banno E, Takao T, Takada S, Yachida S, Uemura H, Nakamura S, Nonomura N.
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 8 Pages: 3125-3135

    • DOI

      10.1111/cas.14998

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Firmicutes/Bacteroidetes ratio of the human gut microbiota is associated with prostate enlargement.2021

    • Author(s)
      Takezawa K, Fujita K, Matsushita M, Motooka D, Hatano K, Banno E, Shimizu N, Takao T, Takada S, Okada K, Fukuhara S, Kiuchi H, Uemura H, Nakamura S, Kojima Y, Nonomura N.
    • Journal Title

      Prostate

      Volume: 81 Issue: 16 Pages: 1287-1293

    • DOI

      10.1002/pros.24223

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum core-type fucosylated prostate-specific antigen index for the detection of high-risk prostate cancer.2021

    • Author(s)
      Fujita K, Hatano K, Tomiyama E, Hayashi Y, Matsushita M, Tsuchiya M, Yoshikawa T, Date M, Miyoshi E, Nonomura N.
    • Journal Title

      Int J Cancer.

      Volume: Epub ahead of print Issue: 12 Pages: 1-8

    • DOI

      10.1002/ijc.33517

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Influence of Diet and Nutrition on Prostate Cancer.2020

    • Author(s)
      Matsushita M, Fujita K, Nonomura N.
    • Journal Title

      Int J Mol Sci.

      Volume: 21 Issue: 4 Pages: 1447-1464

    • DOI

      10.3390/ijms21041447

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] The role of actinin-4 (ACTN4) in exosomes as a potential novel therapeutic target in castration-resistant prostate cancer.2020

    • Author(s)
      Ishizuya Y, Uemura M, Narumi R, Tomiyama E, Koh Y, Matsushita M, Nakano K, Hayashi Y, Wang C, Kato T, Hatano K, Kawashima A, Ujike T, Fujita K, Imamura R, Adachi J, Tomonaga T, Nonomura N.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 523 Issue: 3 Pages: 588-594

    • DOI

      10.1016/j.bbrc.2019.12.084

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.2020

    • Author(s)
      Fujita K, Kato T, Hatano K, Kawashima A, Ujike T, Uemura M, Imamura R, Okihara K, Ukimura O, Miki T, Nakajima T, Kaneda Y, Nonomura N.,
    • Journal Title

      Cancer Sci.

      Volume: in press Issue: 5 Pages: 1692-1698

    • DOI

      10.1111/cas.14366

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Application of Anti-Inflammatory Agents in Prostate Cancer.2020

    • Author(s)
      Hatano K, Fujita K, Nonomura N.
    • Journal Title

      J Clin Med.

      Volume: 9 Issue: 8 Pages: 2680-2706

    • DOI

      10.3390/jcm9082680

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer.2020

    • Author(s)
      Koh Y, Kawashima A, Ujike T, Nagahara A, Fujita K, Kiuchi H, Imamura R, Miyagawa Y, Nonomura N, Uemura M.
    • Journal Title

      Anticancer Drugs.

      Volume: 31 Issue: 10 Pages: 1099-1102

    • DOI

      10.1097/cad.0000000000000986

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Obesity, Inflammation, and Prostate Cancer.2019

    • Author(s)
      Fujita K, Hayashi T, Matsushita M, Uemura M, Nonomura N.
    • Journal Title

      J Clin Med.

      Volume: 8 Issue: 2 Pages: 201-25

    • DOI

      10.3390/jcm8020201

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate Cancer.2019

    • Author(s)
      Hayashi T, Fujita K, Matsushita M, Nonomura N.
    • Journal Title

      Cancers (Basel).

      Volume: 11 Issue: 8 Pages: 1153-1168

    • DOI

      10.3390/cancers11081153

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Metformin inhibits prostate cancer growth induced by high-fat diet in Pten-deficient model mice2018

    • Author(s)
      Takuji Hayashi, Kazutoshi Fujita, Makoto Matsushita, Yujiro Hayashi, Motohide Uemura, Norio Nonomura
    • Journal Title

      International Journal of Urology

      Volume: 26 Issue: 2 Pages: 307-309

    • DOI

      10.1111/iju.13847

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 腸内細菌と癌、Gut microbiota associated with high-grade prostate cancer2021

    • Author(s)
      藤田 和利、松下 慎、元岡 大祐、波多野 浩士、西本 光寿、坂野 恵里、南 高文、野澤 昌弘、高尾 徹也、高田 晋吾、吉村 一宏、谷内田 真一、中村 昇太、植村 天受、野々村祝夫
    • Organizer
      第80回癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Gut microbiome and prostate cance2021

    • Author(s)
      Kazutoshi Fujita, Makoto Matsushita, Eri Banno, Shota Nakamura, Hirotsugu Uemura, and Norio Nonomura
    • Organizer
      The East Asia Urological Oncology Society 2021 Annual Meeting
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 日本人における高悪性度前立腺癌に特徴的な腸内細菌叢の解析2021

    • Author(s)
      藤田和利、松下慎、波多野浩士、中村昇太、川村憲彦、高田晋吾、西本光寿、坂野恵里、南高文、野澤昌弘、吉村一宏、植村天受、野々村祝夫
    • Organizer
      第109回日本泌尿器科学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 腸内細菌叢による前立腺癌増殖促進メカニズム2021

    • Author(s)
      藤田和利、松下 慎、香山尚子、元岡大祐、長谷拓明、神宮司健太郎、波多野浩士、坂野恵里、デベラスコ マルコ、南高文、野澤昌弘、吉村一宏、辻川和丈、中村昇太、竹田 潔 、野々村祝夫, 植村天受
    • Organizer
      第34回日本バイオセラピィ学会学術集会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] GUT MICROBIOTA PROFILE ASSOCIATED WITH HIGH-GRADE PROSTATE CANCER2021

    • Author(s)
      Kazutoshi Fujita, Makoto Matsushita, Daisuke Motooka, Koji Hatano, Shota Fukae, Norihiko Kawamura, Eisuke Tomiyama, Yujiro Hayashi, Eri Banno, Tetsuya Takao, Shingo Takada, Shinichi Yachida, Takafumi Minami, Masahiro Nozawa, Kazuhiro Yoshimura, Hirotsugu Uemura, Shota Nakamura, and Norio Nonomura
    • Organizer
      The 116th AUA annual meeting 2021
    • Related Report
      2021 Annual Research Report
  • [Presentation] 高脂肪食摂取前立腺癌モデルマウスの前立腺組織の網羅的遺伝子発現解析による、高脂肪食が促進する癌増殖メカニズムの解明2021

    • Author(s)
      松下 慎、藤田和利、林 拓自、冨山栄輔、洪 陽子、中野剛佑、林裕次郎、加藤大悟、波多野浩士、河嶋厚成、氏家 剛、福原慎一郎、木内 寛、植村元秀、辻川和丈、野々村祝夫
    • Organizer
      日本アンドロロジー学会第39回学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 前立腺癌モデルマウスにおいてヒスタミンはH1レセプタを介して高脂肪食による癌の増殖に関与する2020

    • Author(s)
      松下 慎, 藤田 和利, 弓場 覚, 冨山 栄輔, 洪 陽子, 林 裕次郎, 中野 剛佑, 神宮司 健太郎, 加藤 大悟, 波多野 浩士, 河嶋 厚成, 氏家 剛, 植村 元秀, 辻川 和丈, 森井 英一, 野々村 祝夫
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 自動化マイクロキャピラリー電気泳動法による高Gleason前立腺癌診断法のための血中Core型フコシル化PSA測定法の開発2020

    • Author(s)
      藤田 和利, 林 裕次郎, 吉川 友康, 山下 謙一郎, 冨山 栄輔, 松下 慎, 中野 剛佑, 加藤 大悟, 波多野 浩士, 河嶋 厚成, 氏家 剛, 植村 元秀, 吉村 一宏, 植村 天受, 三善 英知, 野々村 祝夫
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 前立腺特異的Ptenノックアウトマウスの前立腺癌組織の網羅的遺伝子発現解析による高脂肪食がもたらす癌増大に関与する遺伝子の探索2020

    • Author(s)
      松下 慎、藤田和利、林 拓自、冨山栄輔、洪 陽子、石津谷祐、王 聡、加藤大悟、波多野浩士、河嶋厚成、氏家 剛、植村元秀、野々村祝夫
    • Organizer
      第108回日本泌尿器科学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] マイクロキャピラリー電気泳動免疫蛍光測定装置による血清Core型フコシル化PSA測定法の開発2020

    • Author(s)
      藤田和利、吉川友康、山下謙一郎、冨山栄輔、松下 慎、加藤大悟、波多野浩士、河嶋厚成、氏家 剛、植村元秀、三好英知、野々村祝夫
    • Organizer
      第108回日本泌尿器科学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 臨床的意義のある前立腺癌の診断における再生検時の前立腺multiparametric MRIの有用性2020

    • Author(s)
      波多野浩士、加藤大悟、氏家 剛、藤田和利、植村元秀、野々村祝夫
    • Organizer
      第108回日本泌尿器科学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 前立腺癌発症モデルマウスにおける、高脂肪食による 腫瘍増殖に対するメトホルミンの抑制効果の検討2019

    • Author(s)
      松下 慎、藤田和利、林 拓自、洪 陽子、中野剛佑、林裕次郎、石津谷祐、加藤大悟、河嶋厚成、氏家 剛、永原 啓、植村元秀、野々村祝夫
    • Organizer
      第107回日本泌尿器科学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 前立腺癌自然発症モデルマウスにおいてメトホルミンが高脂肪食による前立腺癌の増殖を抑制する2019

    • Author(s)
      松下 慎、藤田和利、林 拓自、洪 陽子、中野剛佑、林裕次郎、石津谷裕、加藤大悟、河嶋厚成、氏家 剛、永原 啓、福原慎一郎、木内 寛、植村元秀、野々村祝夫
    • Organizer
      第38回日本アンドロロジー学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Metformin inhibits cancer growth induced by high-fat diet in a mouse Pten-deficient prostate cancer model2019

    • Author(s)
      Makoto Matsushita, Kazutoshi Fujita, Takuji Hayashi, Yujiro Hayashi, Kosuke Nakano, Yu Ishizuya, Cong Wang, Taigo Kato, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Motohide Uemura, Norio Nonomura
    • Organizer
      第78回日本癌学
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 前立腺がんを検査する方法2020

    • Inventor(s)
      野々村祝夫
    • Industrial Property Rights Holder
      野々村祝夫
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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