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Construction of therapeutic methods targeting ADAM9 expressed in cancer-related fibroblasts and search for new target molecules

Research Project

Project/Area Number 21K06958
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionNational Defense Medical College

Principal Investigator

Mochizuki Satsuki  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 外科学, 講師 (80365428)

Co-Investigator(Kenkyū-buntansha) 上野 秀樹  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 外科学, 教授 (90597535)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsADAM / ECM / 癌微小環境 / 癌関連線維芽細胞 / 線維性癌間質反応 / 大腸癌 / がん関連線維芽細胞 / CAF / TIMP / DR / PDC / 低分化胞巣 / オルガノイド / ADAM12 / Desmoplastic reaction / ADAM9s / ADAM9 / 細胞外マトリックス
Outline of Research at the Start

当教室では、大腸癌症例を癌細胞浸潤先端部の間質構造の違いから、類粘液性間質と不規則な膠原線維を特徴とするImmature型、類粘液性間質を認めずケロイドで出現するヒアリン化膠原線維が存在するIntermediate 型、繊細な膠原線維が配列した線維性構造からなるMature型に分類 (Desmoplastic reaction: DR分類) し、予後との関係性を検討した結果、手術後の予後はMature型、Intermediate型、Immature型の順に不良となることが明らとなっている。本研究では、DR分類が予後因子となる理由を調べるため、大腸癌手術検体からCAFや大腸癌オルガノイド培養を行い、ADAM分子の網羅的発現と機能解析について検討を行う。

Outline of Final Research Achievements

Desmoplastic reaction (DR), which is morphologically classified to Mature, Intermediate and Immature types, is correlated with patient prognosis. Conditioned media of CAFs from tumor with Immature type DR (CAFsImmature) significantly increased proliferation and migration of CRC cells compared to those of CAFs from Mature-type DR (CAFsMature). Subcutaneous implantation of CRC cells together with CAFsImmature in mice significantly promoted tumor growth and peritoneal dissemination compared to those with CAFsMature. Systematic examination indicated that ADAM9s expression is significantly higher in CAFsImmature than in CAFsMature. Knockdown of ADAM9s in CAFsImmature suppressed the promoting effects on CRC cell proliferation and migration. ADAM9s overproduced by CAFsImmature has been suggested to promote CRC cell proliferation and migration, suggesting an impact on poor prognosis of patients with Immature-type DR.

Academic Significance and Societal Importance of the Research Achievements

本研究による研究成果は、「 Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness」のタイトルでInt J Cancer 15: 1706-1721, 2022 誌に責任著者として発表し、本論文は2022年度日本結合組織学会大高賞を受賞した。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (14 results)

All 2023 2022 2021

All Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (5 results) (of which Int'l Joint Research: 1 results) Book (2 results)

  • [Journal Article] Periostin derived from cancer-associated fibroblasts promotes esophageal squamous cell carcinoma progression via ADAM17 activation.2023

    • Author(s)
      Yusuke Ishibashi, Satsuki Mochizuki *, Keisuke Horiuchi, Hironori Tsujimoto, Keita Kouzu, Yoji Kishi , Yasunori Okada and Hideki Ueno
    • Journal Title

      BBA-Molecular Basis of Disease

      Volume: 1869 Issue: 5 Pages: 166669-166669

    • DOI

      10.1016/j.bbadis.2023.166669

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prognostic impact of desmoplastic reaction in esophageal squamous cell carcinoma patients with neoadjuvant therapy2023

    • Author(s)
      Kouzu Keita、Kajiwara Yoshiki、Tsujimoto Hironori、Mochizuki Satsuki、Okamoto Koichi、Shinto Eiji、Kishi Yoji、Matsukuma Susumu、Ueno Hideki
    • Journal Title

      Esophagus

      Volume: 20 Issue: 3 Pages: 474-483

    • DOI

      10.1007/s10388-023-00996-z

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM92022

    • Author(s)
      Ao T, Mochizuki S, Kajiwara Y, Yonemura K, Shiraishi T, Nagata K, Shinto E, Okamoto K, Nearchou IP, Shimazaki H, Kishi Y, Okada Y, Ueno H
    • Journal Title

      Int J Cancer

      Volume: 150 Issue: 10 Pages: 1706-1721

    • DOI

      10.1002/ijc.33947

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synergistic upregulation of ADAMTS4 (aggrecanase-1) by cytokines and its suppression in knee osteoarthritic synovial fibroblasts2021

    • Author(s)
      Cilek Mehmet Zeynel、de Vega Susana、Shiozawa Jun、Yoshinaga Chiho、Miyamae Yuka、Chijiiwa Miyuki、Mochizuki Satsuki、Ito Masatoshi、Kaneko Haruka、Kaneko Kazuo、Ishijima Muneaki、Okada Yasunori
    • Journal Title

      Laboratory Investigation

      Volume: 102 Issue: 1 Pages: 102-111

    • DOI

      10.1038/s41374-021-00685-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mesothelin Expression is Correlated with Chemoresistance in Stage IV Colorectal Cancer2021

    • Author(s)
      Nagata K, Shinto E, Shiraishi T, Yamadera M, Kajiwara Y, Mochizuki S, Okamoto K, Einama T, Kishi Y, Ueno H.
    • Journal Title

      Ann Surg Oncol .

      Volume: 28 Issue: 13 Pages: 8579-8586

    • DOI

      10.1245/s10434-021-10507-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] How has the COVID-19 pandemic affected gastrointestinal surgery for malignancies and surgical infections?2021

    • Author(s)
      Ishibashi Y, Tsujimoto H, Sugasawa H, Mochizuki S, Okamoto K, Kajiwara Y, Shinto E, Takahata R, Kobayashi M, Fujikura Y, Hase K, Kishi Y, Ueno H.
    • Journal Title

      Nagoya Journal of Medical Science

      Volume: 83 Issue: 4 Pages: 715-725

    • DOI

      10.18999/nagjms.83.4.715

    • NAID

      120007174356

    • ISSN
      0027-7622
    • URL

      https://nagoya.repo.nii.ac.jp/records/2001654

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Periostin as a key molecule defining desmoplastic environment in colorectal cancer2021

    • Author(s)
      Takahiro Sueyama , Yoshiki Kajiwara , Satsuki Mochizuki , Hideyuki Shimazaki , Eiji Shinto , Kazuo Hase , Hideki Ueno
    • Journal Title

      Virchows Arch

      Volume: 478 Issue: 5 Pages: 865-874

    • DOI

      10.1007/s00428-020-02965-8

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] 食道扁平上皮癌のがん関連線維芽細胞(CAFs)はPeriostinを分泌して癌細胞の増殖・遊走を促進する2023

    • Author(s)
      望月早月、石橋勇輔、堀内圭輔、辻本広紀、岸庸二、岡田保典、上野秀樹
    • Organizer
      第112回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ADAM12による大腸癌低分化胞巣形成機構の解析と治療への応用2023

    • Author(s)
      望月早月、川内隆幸、米村圭介、梶原由規、阿尾理一、岡田保典、上野秀樹
    • Organizer
      第34回日本消化器癌発生学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ADAM9s and periostin derived from cancer-associated fibroblasts are involved in alimentary tract cancer progression2022

    • Author(s)
      Satsuki Mochizuki
    • Organizer
      2022 Korea-Japan Joint Symposium on Matrix Biology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] 大腸癌線維性癌間質反応におけるメタロプロテアーゼADAM9の役割2021

    • Author(s)
      望月早月
    • Organizer
      第26回日本病態プロテアーゼ学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Periostinは食道扁平上皮癌においてADAM17の活性化と癌細胞増殖・浸潤能を促進する2021

    • Author(s)
      石橋勇輔、望月早月、辻本広紀、堀内圭輔、 若松高太郎、菅澤英一、岸庸二、上野秀樹
    • Organizer
      第53回日本結合組織学会学術大会
    • Related Report
      2021 Research-status Report
  • [Book] 別冊医学のあゆみ 臓器線維症を科学するー病態解明と治療法開発への展望2021

    • Author(s)
      望月早月、岡田保典
    • Total Pages
      6
    • Publisher
      医歯薬出版
    • Related Report
      2021 Research-status Report
  • [Book] これだけは読んでおきたい消化器外科医のための重要論文223篇2021

    • Author(s)
      望月早月
    • Total Pages
      4
    • Publisher
      シービーアール
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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