C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA

Abstract

PurposeAnaphylatoxin C5a is a strong chemoattractant of the complement system that binds the C5a receptor (C5aR). The expression of C5aR is associated with poor prognosis in several cancers. However, the role of C5aR in gastric cancer (GC) is unknown. The aim of this study was to examine the role of C5aR on GC cell motility and invasion.Experimental DesignThe mechanism of invasion via C5aR was assessed by analyzing cytoskeletal rearrangement and RhoA activity after C5a treatment. Moreover, we investigated the relationship between C5aR expression and the prognosis of GC patients.ResultsTwo human GC cell lines (MKN1 and MKN7) had high C5aR expression. An invasion assay revealed that C5a stimulation promoted the invasive ability of MKN1 and MKN7 cells and that this was suppressed by knockdown of C5aR using siRNA or a C5aR-antagonist. Moreover, overexpression of C5aR in GC cells enhanced the conversion of RhoA-guanosine diphosphate (RhoA-GDP) to RhoA-guanosine triphosphate (RhoA-GTP) after C5a stimulation and caused morphological changes, including increased expression of stress fibers and filopodia. Examination of tumor specimens from 100 patients with GC revealed that high C5aR expression (35 of 100 samples, 35.0%) was associated with increased invasion depth, vascular invasion and advanced stage. The 5-year overall survival of patients with high or low C5aR expression was 58.2% and 88.5%, respectively (p=0.008).ConclusionsThis study is the first to demonstrate that C5aR promotes GC cell invasion by activating RhoA and is associated with a poor prognosis in GC patients. Therefore, this study provides a biomarker for GC patients who require an advanced therapeutic strategy.

Novel mechanisms and functions of complement

“…Complement also promotes tumor cell motility and invasiveness through induction of metalloproteinases from tumor cells, degradation of extracellular matrix and increased expression of stress fibers and filopodia 104-106 . C3aR signaling, for instance, is implicated in the dissemination of cancer to the nervous system by disrupting the blood-cerebrospinal fluid barrier 107 .…”

Complement in cancer: untangling an intricate relationship

“…Aberrant expression of C5aR1 has been detected in squamous cell carcinoma, adenocarcinoma and transitional cell carcinoma from various organs, and vascular invasion appears to be correlated with the expression of C5aR1 (REFS 67,92,93 ). Cell invasiveness has been shown to occur in response to C5a-induced secretion of metalloproteinases from C5aR1-expressing cancer cells and degradation of ECM 68 .…”

“…In addition, leukaemia cell lines as well as clonogenic blasts derived from patients with chronic myeloid leukaemia or acute myeloid leukaemia show increased cell adhesion in response to C3a and C5a fragments 95 . In a model of gastric cancer, C5a promoted the invasiveness of human gastric cancer cell lines (the adenosquamous carcinoma cell line MKN1 and the tubular adenocarcinoma cell line MKN7) via conversion of RhoA-guanosine diphosphate (RhoA-GDP) to RhoA-guanosine triphosphate (RhoA-GTP), resulting in morphological cell changes and increased expression of stress fibres and filopodia 92 .…”

C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma

“…Because C5aRs have been reported to be expressed by a range of human and murine tumor cell types (14,29,30), we next investigated receptor expression by B16.F0 melanoma cells. Quantitative PCR (qPCR) analysis showed that cultured B16.F0 cells express mRNA for C5aR1 and C5aR2, albeit at much lower levels than in J774 macrophages (Fig.…”