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

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10537
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto 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
• Keywords: ケモカイン / 大腸癌 / 転移 / 骨髄由来細胞

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.

Free Research Field

小腸大腸肛門外科学

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。