Complement 5a stimulates macrophage polarization and contributes to tumor metastases of colon cancer
Complement 5a stimulates macrophage polarization and contributes to tumor metastases of colon cancer
复制标题
补体 5a 刺激巨噬细胞极化并导致结肠癌肿瘤转移
DOI：
10.1016/j.yexcr.2018.03.009
复制
发表时间：
2018-05-15
影响因子：
3.7
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Piao, Chunmei;Zhang, Wen-Mei;Du, Jie
巨噬细胞等炎症细胞在肿瘤间质中可发挥促肿瘤发生的作用。肿瘤相关巨噬细胞（TAMs）通常呈现具有促肿瘤活性的M2表型；然而，调控TAM表型的机制仍不明确。补体5a（C5a）是一种细胞因子样多肽，在补体系统激活过程中产生，已知其可促进肿瘤生长。在此，我们研究了C5a在小鼠结肠癌转移过程中对巨噬细胞极化的作用。我们发现，C5a受体（C5aR）缺失会严重损害植入的结肠癌细胞的转移能力。C5aR在TAMs上表达，在结肠癌肝转移病灶中，这些TAMs呈现出类似M2的功能特征。此外，C5a介导巨噬细胞极化，且这一过程在很大程度上依赖于核因子-κB（NF-κB）通路的激活。最后，对人类结肠癌的分析表明，C5aR的表达与肿瘤分化程度呈负相关。我们的研究结果表明，C5aR在调控TAMs的M2表型中起核心作用，进而通过NF-κB信号通路促进结肠癌的肝转移。C5a是一种潜在的新型癌症预后标志物，针对补体系统激活（特别是C5aR通路）的药物，可能为结肠癌的治疗提供新的契机。
Inflammatory cells such as macrophages can play a pro-tumorigenic role in the tumor stroma. Tumor-associated macrophages (TAMs) generally display an M2 phenotype with tumor-promoting activity; however, the mechanisms regulating the TAM phenotype remain unclear. Complement 5a (C5a) is a cytokine-like polypeptide that is generated during complement system activation and is known to promote tumor growth. Herein, we investigated the role of C5a on macrophage polarization in colon cancer metastasis in mice. We found that deficiency of the C5a receptor (C5aR) severely impairs the metastatic ability of implanted colon cancer cells. C5aR was expressed on TAMs, which exhibited an M2-like functional profile in colon cancer liver metastatic lesions. Furthermore, C5a mediated macrophage polarization and this process relied substantially on activation of the nuclear factor-kappa B (NF-kappa B)pathway. Finally, analysis of human colon carcinoma indicated that C5aR expression is negatively associated with tumor differentiation grade. Our results demonstrate that C5aR has a central role in regulating the M2 phenotype of TAMs, which in turn, contributes to hepatic metastasis of colon cancer through NF-kappa B signaling. C5a is a potential novel marker for cancer prognosis and drugs targeting complement system activation, specifically the C5aR pathway, may offer new therapeutic opportunities for colon cancer management.