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论文题目: Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
英文论文题目: Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
第一作者: Li, XG; Yao, WB; Yuan, Y; Chen, PZ; Li, B; Li, JQ; Chu, RA; Song, HY; Xie, D; Jiang, XQ; Wang, H
英文第一作者: Li, XG; Yao, WB; Yuan, Y; Chen, PZ; Li, B; Li, JQ; Chu, RA; Song, HY; Xie, D; Jiang, XQ; Wang, H
联系作者: Wang, H (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, 320 YueYang Rd, Shanghai 200031, Peoples R China.
英文联系作者: Wang, H (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, 320 YueYang Rd, Shanghai 200031, Peoples R China.
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发表年度: 2017
卷: 66
期: 1
页码: 157-167
摘要: Objective Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC. Design CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells. Result CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8(+) T cell response. Conclusions In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.
英文摘要: Objective Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC. Design CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells. Result CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8(+) T cell response. Conclusions In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.
刊物名称: GUT
英文刊物名称: GUT
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学科: Gastroenterology & Hepatology
英文学科: Gastroenterology & Hepatology
影响因子: 16.658
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论文类别: Article
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