Enhancement of human cancer cell migration and invasion by anaphylatoxin C5a viaaberrantly expressed C5a-receptor.

Abstract

e21084 Background: Accumulated evidence has revealed implications of chemokines and their receptors in the pathophysiology of cancer. Anaphylatoxin C5a, a fragment of the complement 5th component (C5), is a potent chemokine for leukocytes that express the C5a receptor (C5aR). Recent reports indicate production of C5a by proteases of various origins, besides a by-product of activation of the complement system, and expression of C5aR in non-myeloid cells, suggesting an involvement of C5a in these cell biology. However, little is known about roles of C5aR in human cancer. Aim of our study was to investigate the expression and the role of C5aR on cancer cells in proliferation and invasion. Methods: Surgically resected cancer tissues and cancer cell lines were investigated C5aR expression. The effect of C5a on cancer cell proliferation, cell shape and invasion activity were examined in vitro and in vivo. Results: By immunohistochemical analysis, C5aR was strongly expressed in human cholangiocarcinoma samples. Using RT-PCR, immunoblotting and flow cytometric analysis human cholangiocarcinoma cell line MEC but not HuCCT1 were found to express C5aR. Incubation of both cancer cells with C5a did not increase these cells, indicating no mitogenic effect of C5a on these cells. Interestingly, C5a stimulated invasion of MEC and C5aR-transgenic HuCCT1 when examined by Matrigel invasion assay, which was suppressed by anti C5aR antibody. F-actin staining and human MMPs array revealed that C5a induced actin polymerization and MMPs production, respectively, in MEC and C5aR-transgenic HuCCT1. In contrast, these C5a effects were not seen in HuCCT1. Conclusions: These results illustrate a novel activity of C5a-C5aR axis that promotes cancer cell invasion through cytoskeletal rearrangement and MMP release. Thus, targeting this signaling pathway may provide a useful therapeutic option for cancer treatment.