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补体影响肿瘤微环境 促进结肠癌肝转移

来源:生物谷 2015-04-29 09:55

                                                                  

2015年4月29日讯 /生物谷BIOON/ --近日,来自首都医科大学附属安贞医院的研究人员在国际学术期刊journal of biological chemistry发表了关于结肠癌肝转移的最新研究结果,在该文章中,他们发现补体5a(c5a)能够通过趋化因子mcp-1介导的炎症浸润促进结肠癌细胞向肝脏转移。
 
补体5a是补体激活过程产生的强力免疫调节因子,有研究发现c5a在促进肿瘤生长方面具有重要作用,但其在肿瘤转移方面的作用一直未有研究。在该文章中,研究人员发现c5a能够通过调节结肠癌肝转移灶中的肿瘤免疫促进肿瘤转移灶形成。
 
结肠癌细胞在无血清培养条件下能够产生c5a,而在结肠癌肝转移小鼠模型中,c5a的表达水平也显著增加。当缺失c5a受体或通过anti-c5单克隆抗体抑制c5a产生,肿瘤转移过程会受到严重损伤。在缺少c5a受体的结肠癌转移灶,巨噬细胞,中性粒细胞和树突状细胞的浸润现象显著下降,研究人员也通过骨髓移植实验证明了c5a受体在这些细胞中的作用。同时,c5a信号能够增加趋化因子mcp-1以及抗炎症分子精氨酸酶1,IL-10,TGFβ的表达,但与促炎症分子的表达呈负相关。这表明c5a可能在肿瘤转移的炎症微环境形成方面具有重要作用。
 
综上所述,这项研究发现补体c5a能够通过影响肿瘤转移灶炎症微环境形成促进肿瘤转移,提示我们靶向补体c5a可能是治疗恶性肿瘤的一种潜在治疗策略。(生物谷Bioon.com)
 
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Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration*
 
Chunmei Piao, Lun Cai, Shulan Qiu, Lixin Jia, Wenchao Song and Jie Du
 
Complement 5a (C5a), a potent immune mediator generated by complement activation, promotes tumor growth; however, its role in tumor metastasis remains unclear. We demonstrate that C5a contributes to tumor metastases by modulating tumor inflammation in hepatic metastases of colon cancer. Colon cancer cell lines generate C5a under serum-free conditions, and C5a levels increase over time in a murine syngeneic colon cancer hepatic metastasis model. Furthermore, in the absence of C5a receptor or upon pharmacological inhibition of C5a production with an anti-C5 monoclonal antibody, tumor metastasis is severely impaired. A lack of C5a receptor in colon cancer metastatic foci reduces the infiltration of macrophages, neutrophils, and dendritic cells, and the role for C5a receptor on these cells were further verified by bone marrow transplantation experiments. Moreover, C5a signaling increases the expression of the chemokine monocyte chemoattractant protein-1 and the anti-inflammatory molecules arginase-1, interleukin 10, and transforming growth factor β, but is inversely correlated with the expression of pro-inflammatory molecules, which suggests a mechanism for the role of C5a in the inflammatory microenvironment required for tumor metastasis. Our results indicate a new and potentially promising therapeutic application of complement C5a inhibitor for the treatment of malignant tumors.
 
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