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Elucidation of tumor microenvironmental via expression of TDO in liver metastasis of colorectal cancer and its clinical application

Research Project

Project/Area Number 16K10560
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Digestive surgery
Research InstitutionNational Cancer Center Japan

Principal Investigator

Miyazaki Toshiaki  国立研究開発法人国立がん研究センター, 研究所, 研究員 (50589075)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywords大腸がん / 肝転移 / Kynurenine / TDO2 / kynurenine / がん幹細胞 / 転移 / がん免疫 / がん微小環境
Outline of Final Research Achievements

Cancer stem cells (CSC) represent a small fraction of cancer cells and are associated with malignant traits of cancer such as tumorigenesis and metastasis. Elucidation of the biological nature of CSCs will be important to understand the refractory traits of cancer and to devise new strategies for cancer therapy. In an attempt to identify biochemical alterations associated with metastatic traits of cancer, we compared metabolic profiles of spheroids established from CSCs derived from non-metastatic cancers and metastatic foci. We found that Kynurenine was up-regulated in spheroids derived from metastasized liver. In accordance, levels of TDO2, an enzyme responsible for Kynurenine production, were higher in metastatic CSCs than in non-metastatic ones. TDO2 over-expression promoted liver metastasis and suppressed accumulation of immune cells around the metastatic lesion. These results indicate that TDO2 plays an important role in liver metastasis though Kynurenine production.

Academic Significance and Societal Importance of the Research Achievements

キヌレニンの合成を担うTDO2はがん細胞内で発現が上昇しているが、未だキヌレニンやTDOのin vivoにおける免疫抑制やがん細胞転移の作用メカニズムの解明は十分ではない。本研究によりTDO2は、キヌレニンの産生増加、免疫系の制御を介して、大腸がん転移を促進させることを新たに明らかにした。キヌレニンやTDOがもたらす微小環境変化と転移メカニズムの関係が明らかになることにより、TDOとキヌレニンをターゲットとした診断マーカーならびに、新規分子標的の発見により臨床への応用に貢献することができる可能性があると考える。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (9 results)

All 2018 2017

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (8 results)

  • [Journal Article] Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression2018

    • Author(s)
      Miyazaki Toshiaki、Ikeda Kazuhiro、Sato Wataru、Horie-Inoue Kuniko、Inoue Satoshi
    • Journal Title

      Oncogenesis

      Volume: 7 Issue: 1 Pages: 7-7

    • DOI

      10.1038/s41389-017-0022-6

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 大腸がん幹細胞のメタボローム解析による肝転移メカニズムの解明2018

    • Author(s)
      宮崎 利明
    • Organizer
      第1回 がんと代謝研究会・若手の会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Elucidation of novel mechanism of liver metastasis of colon cancer through metabolome analyses of cancer stem cells2018

    • Author(s)
      宮崎 利明
    • Organizer
      第27回 日本がん転移学会 学術集会・総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 大腸がん幹細胞のメタボローム解析による新規肝転移メカニズムの解明2018

    • Author(s)
      宮崎 利明
    • Organizer
      第33回発癌病理研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Elucidation of novel mechanism of liver metastasis of colon cancer through metabolome analyses of cancer stem cells2018

    • Author(s)
      宮崎 利明
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 大腸がん幹細胞のメタボローム解析による肝転移メカニズムの解明2018

    • Author(s)
      宮崎 利明、大畑 広和、曽我 朋義、岡本 康司
    • Organizer
      第1回 がんと代謝研究会・若手の会
    • Related Report
      2017 Research-status Report
  • [Presentation] 大腸がん幹細胞のメタボローム解析による肝転移メカニズムの解明2017

    • Author(s)
      宮崎 利明、大畑 広和、岡本 康司
    • Organizer
      第5回がんと代謝研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 大腸がん幹細胞のメタボローム解析による肝転移メカニズムの解明2017

    • Author(s)
      宮崎 利明、大畑 広和、岡本 康司
    • Organizer
      第32回発癌病理研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] Elucidation of novel mechanism of liver metastasis of colon cancer through metabolome analyses of cancer stem cells2017

    • Author(s)
      Toshiaki Miyazaki, Hirokazu Ohata, Koji Okamoto
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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