| Project/Area Number |
16K10537
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Kyoto University |
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Principal Investigator |
KAWADA KENJI 京都大学, 医学研究科, 講師 (90322651)
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| Research Collaborator |
TAKETO makoto
HIRAI hideyo
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| 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)
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| 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 |
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| 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.
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| 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。
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