Abstract
The anaphylatoxin C5a is a chemoattractant that induces leukocyte migration via C5a receptor (C5aR). There is emerging evidence that C5a is generated in the cancer microenvironment. We therefore sought C5aR expression and a direct influence of the C5a-C5aR axis on cancer cells. C5aR expression was investigated in human cancer tissues and cell lines. Effects of C5a stimulation on cancer cells were studied by cytoskeletal rearrangement, time-lapse analysis, Matrigel chamber assay, and invasion in nude mouse in a comparison of C5aR-expressing cancer cells with control cells. C5aR was aberrantly expressed in various human cancers. Several cancer cell lines also expressed C5aR. C5a triggered cytoskeletal rearrangement and enhanced cell motility three-fold and invasiveness 13-fold of C5aR-expressing cancer cells. Such enhancement by C5a was not observed in control cells. Cancer cell invasion was still enhanced in the absence of C5a concentration gradient and even after the removal of C5a stimulation, suggesting that random cell locomotion plays an important role in C5a-triggered cancer cell invasion. C5a increased the release of matrix metalloproteinases (MMP) from cancer cells by two- to 11-fold, and inhibition of MMP activity abolished the C5a-enhancing effect on cancer cell invasion. Compared with control cells, C5aR-expressing cells spread 1.8-fold more broadly at implanted nude mouse skin sites only when stimulated with C5a. These results illustrate a novel activity of the C5a-C5aR axis that promotes cancer cell invasion through motility activation and MMP release. Targeting this signaling pathway may provide a useful therapeutic option for cancer treatment.
Highlights
The complement system is a biochemical cascade involved in immune responses [1]
Cancer cell invasion was still enhanced in the absence of C5a concentration gradient and even after the removal of C5a stimulation, suggesting that random cell locomotion plays an important role in C5a-triggered cancer cell invasion
C5a increased the release of matrix metalloproteinases (MMP) from cancer cells by two- to 11-fold, and inhibition of MMP activity abolished the C5a-enhancing effect on cancer cell invasion
Summary
The complement system is a biochemical cascade involved in immune responses [1]. Previous reports showed that the complement system is activated on cancer cells in both an animal model [2] and in tissue specimensAuthors' Affiliations: Departments of 1Molecular Pathology, 2Gastroenterological Surgery, 3Urology, 4Immunogenetics, and 5Tumor Genetics and Biology, Faculty of Life Sciences, Kumamoto University; 6Medical Quality Management Center, Kumamoto University Hospital, Kumamoto; 7Yakult Central Institute for Microbiological Research, Tokyo; and 8Department of Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, JapanNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Y. The complement system is a biochemical cascade involved in immune responses [1]. Previous reports showed that the complement system is activated on cancer cells in both an animal model [2] and in tissue specimens. Authors' Affiliations: Departments of 1Molecular Pathology, 2Gastroenterological Surgery, 3Urology, 4Immunogenetics, and 5Tumor Genetics and Biology, Faculty of Life Sciences, Kumamoto University; 6Medical Quality Management Center, Kumamoto University Hospital, Kumamoto; 7Yakult Central Institute for Microbiological Research, Tokyo; and 8Department of Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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