Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration |
| |
Authors: | Chunmei Piao Lun Cai Shulan Qiu Lixin Jia Wenchao Song Jie Du |
| |
Affiliation: | From the ‡Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing 100029 and ;§The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China |
| |
Abstract: | 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. |
| |
Keywords: | Chemokine Complement Macrophage Tumor Metastasis Tumor Microenvironment Complement 5a Monocyte Chemoattractant Protein-1 |
|
|