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Novel strategy focusing on bone marrow-derived cells in the tumor microenvironment

Research Project

Project/Area Number 16K10537
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Digestive surgery
Research InstitutionKyoto University

Principal Investigator

KAWADA KENJI  京都大学, 医学研究科, 講師 (90322651)

Research Collaborator TAKETO makoto  
HIRAI hideyo  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsケモカイン / 大腸癌 / 転移 / 骨髄由来細胞 / 好中球 / 間葉系幹細胞 / 小腸大腸肛門外科学
Outline of Final Research Achievements

In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1+ cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of clinical samples revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive lung metastases recruited more numbers of CCR1+ cells than CCL15-negative metastases. Importantly, CCL15 expression was an independent predictor of shorter relapse-free survival.
We found that CCR5 ligands (i.e., CCL3/4/5) were highly produced from mesenchymal stem cells (MSCs) using a chemokine array screening. The xenografts in which CCR5-overexpressing HCT116 cells were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens, CCR5 expression was associated with patients’ prognosis. Especially, stage III/IV patients exhibited a significantly poorer prognosis.

Academic Significance and Societal Importance of the Research Achievements

大腸癌肺転移では、SMAD4の欠損によりCCL15の発現が誘導されCCR1陽性好中球が転移巣周囲に集積し、肺転移が促進されることが示唆された。肺転移巣周囲に集積するCCR1陽性好中球は大腸癌肺転移にたいする新規の治療ターゲットとなり得る。
CCR5発現は病期の進んだ大腸癌症例において予後不良因子であり、またそのリガンドであるCCL3,CCL4の血清高値は予後不良のバイオマーカーになりえる。大腸癌においてCCR5が新たな治療ターゲットとなり得る可能性が示唆された。

Report

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

    (3 results)

All 2019 2017

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results,  Acknowledgement Compliant: 1 results)

  • [Journal Article] Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8-CXCR2 Axis.2019

    • Author(s)
      Ogawa R, Yamamoto T, Hirai H, Hanada K, Kiyasu Y, Nishikawa G, Mizuno R, Inamoto S, Itatani Y, Sakai Y, Kawada K.
    • Journal Title

      Clinical Cancer Research

      Volume: - Issue: 9 Pages: 2887-2899

    • DOI

      10.1158/1078-0432.ccr-18-3684

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5.2019

    • Author(s)
      Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y.
    • Journal Title

      Cell Death & Disease

      Volume: 10 Issue: 4 Pages: 264-264

    • DOI

      10.1038/s41419-019-1508-2

    • NAID

      120006596558

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-associated Neutrophils through CCL15-CCR1 Axis2017

    • Author(s)
      Yamamoto T, Kawada K, Itatani Y, Inamoto S, Okamura R, Iwamoto M, Miyamoto E, Chen-Yoshikawa TF, Hirai H, Hasegawa S, Date H, Taketo MM, Sakai Y.
    • Journal Title

      Clinical Cancer Research

      Volume: 23 Issue: 3 Pages: 833-844

    • DOI

      10.1158/1078-0432.ccr-16-0520

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant

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

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