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Identification of molecular mechanism underlying peritoneal metastasis progression by tumor stromal cells.

Research Project

Project/Area Number 20K08985
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 55010:General surgery and pediatric surgery-related
Research InstitutionKumamoto University

Principal Investigator

Yasuda Tadahito  熊本大学, 大学院生命科学研究部(医), 特定研究員 (00867947)

Co-Investigator(Kenkyū-buntansha) 石本 崇胤  熊本大学, 病院, 特任准教授 (00594889)
三宅 慧輔  熊本大学, 病院, リサーチ・スペシャリスト (10814759)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords腫瘍微小環境 / 胃癌 / CAFs / EZH2 / 腹膜播種 / 細胞老化 / JAK-STAT阻害剤 / 胃がん
Outline of Research at the Start

癌細胞をとりまく腫瘍間質において線維芽細胞は、癌細胞や周囲の免疫細胞等との相互作用により活性化され、癌関連線維芽細胞(Cancer associated fibroblast: CAFs)として様々な液性因子を分泌し癌進展に関わることが知られている。一方で、切除不能な腹膜播種形成において、CAFsがどのような役割を果たすかについて、未だ分かっていない。本研究の目的は癌関連炎症下で活性化したCAFsの解析により、腹膜播種進展におけるCAFsの意義を明らかにすることである。得られる研究成果は腹膜播種転移巣のCAFsをターゲットとした分子標的の創出につながり、臨床的意義は大きいと考えられる。

Outline of Final Research Achievements

Our study has uncovered a novel mechanism underlying cancer progression, which involves cancer-associated fibroblasts (CAFs) found in cancerous tissue. Our findings demonstrate that systemic inflammation can induce cellular senescence in CAFs, leading to the secretion of senescence-associated proteins (SASPs) that promote cancer progression over an extended period of time. Moreover, we have identified the presence of senescent-CAFs in the cellular fractions of malignant ascites, where they play a critical role in promoting the peritoneal dissemination of gastric cancer. These results suggest the possibility of developing new treatments for patients with peritoneal dissemination, targeting not only cancer cells at the site of dissemination but also the tumor stroma.

Academic Significance and Societal Importance of the Research Achievements

スキルス胃癌は転移を起こしやすく、その多くは腹膜播種を引き起こすことで知られ、極めて予後が悪いとされている。また最近の研究からスキルス胃癌などの線維化の強い癌腫ではCancer associated fibroblasts (CAFs)が腫瘍間質で癌を促進する際に重要な働きをしていることが報告されている。本研究からスキルス胃がんによる腹膜播種患者に対して、腹膜播種転移巣の腫瘍間質によって活性化するシグナルをターゲットとした分子標的の創出につながることが期待できる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (17 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (2 results) Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (9 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results)

  • [Int'l Joint Research] Duke-NUS Medical School(シンガポール)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Duke-NUS Medical School(シンガポール)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Cellular senescence in the tumor microenvironment and context‐specific cancer treatment strategies2023

    • Author(s)
      Yasuda Tadahito、Baba Hideo、Ishimoto Takatsugu
    • Journal Title

      The FEBS Journal

      Volume: 290 Issue: 5 Pages: 1290-1302

    • DOI

      10.1111/febs.16231

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of senescent cells in malignant ascites using mass cytometry and therapeutic strategies focused on cellular senescence2022

    • Author(s)
      安田 忠仁、石本 崇胤
    • Journal Title

      Cytometry Research

      Volume: 32 Issue: 1 Pages: 27-32

    • DOI

      10.18947/cytometryresearch.32.1_27

    • ISSN
      0916-6920, 2424-0664
    • Year and Date
      2022-07-13
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protocol to establish cancer-associated fibroblasts from surgically resected tissues and generate senescent fibroblasts2021

    • Author(s)
      Yasuda T, Koiwa M, Yonemura A, Akiyama T, Baba H, Ishimoto T
    • Journal Title

      STAR Protocols

      Volume: 2 Issue: 2 Pages: 100553-100553

    • DOI

      10.1016/j.xpro.2021.100553

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination2021

    • Author(s)
      Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H, Ishimoto T.
    • Journal Title

      Cell Reports

      Volume: 34 Issue: 8 Pages: 108779-108779

    • DOI

      10.1016/j.celrep.2021.108779

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional diversity of cancer‐associated fibroblasts in modulating drug resistance2020

    • Author(s)
      Bu Luke、Baba Hideo、Yasuda Tadahito、Uchihara Tomoyuki、Ishimoto Takatsugu
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 10 Pages: 3468-3477

    • DOI

      10.1111/cas.14578

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance2020

    • Author(s)
      Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani Jaffer A, Tan Patrick, Baba H, Ishimoto T
    • Journal Title

      Cancer Research

      Volume: 80 Issue: 16 Pages: 3222-3235

    • DOI

      10.1158/0008-5472.can-19-3803

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 腹膜播種形成を促進するがん性腹水中老化細胞の意義2022

    • Author(s)
      安田 忠仁
    • Organizer
      第81回日本癌学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Senescent-CAFs in malignant ascites enhance peritoneal tumor formation2022

    • Author(s)
      Tadahito Yasuda, Mayu Koiwa, Hideo Baba, Takatsugu Ishimoto
    • Organizer
      IGCC2022
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] がん性腹水中senescent-CAFsによる腹膜播種促進メカニズムの解明2021

    • Author(s)
      安田 忠仁、小岩麻由、馬場秀夫、石本崇胤
    • Organizer
      第29回日本癌病態治療研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] 癌性腹水中Senescent-CAFsによる腹膜播種促進メカニズムの解明2021

    • Author(s)
      安田 忠仁、小岩麻由、馬場秀夫、石本崇胤
    • Organizer
      第93回日本胃癌学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 全身性炎症を背景とする病態を制御し、難治癌の克服を目指すトランスレーショナル研究2021

    • Author(s)
      安田 忠仁、小岩麻由、米村敦子、ブルコ、馬場秀夫、石本崇胤
    • Organizer
      第80回日本癌学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 癌性腹水中SASP-CAFsによる腹膜播種促進メカニズムの解明2021

    • Author(s)
      安田 忠仁、小岩麻由、馬場秀夫、石本崇胤
    • Organizer
      第29回JDDW
    • Related Report
      2021 Research-status Report
  • [Presentation] 腫瘍間質細胞によって促進される胃癌腹膜播種進展メカニズムの解明2021

    • Author(s)
      安田 忠仁、小岩麻由、馬場秀夫、石本崇胤
    • Organizer
      第32回日本消化器癌発生学会総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 胃癌由来CAFsの老化と腹膜播種進展機序の解明2020

    • Author(s)
      安田 忠仁、石本崇胤、小岩麻由、米村敦子、三宅慧輔、内原智幸、江藤弘二郎、岩上志朗、馬場祥史、岩槻政晃、吉田直矢、馬場秀夫
    • Organizer
      第120回日本外科学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Gastric cancer CAFs maintain SASP through epigenetic histone modification and enhance peritoneal dissemination2020

    • Author(s)
      Tadahito Yasuda, Mayu Koiwa, Atsuko Yonemura, Keisuke Miyake, Luke Bu, Hideo Baba, and Takatsugu Ishimoto
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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