Use of co-expression of HGF and c-Met to predict peritoneal dissemination established by autocrine HGF/c-Met signaling in gastric cancer.

Abstract

40 Background: Epithelial mesencymal transition (EMT) promotes facilitates migration and invasion of epithelial tumour cells. EMT is induced by growth factors implicated in theses process such as hepatocyte growth factor (HGF). Our aim of this study is whether HGF/c-Met pathway is associated with metastasis of gastric cancer (GC), especially in peritoneal dissemination (PD). Methods: HGF and c-Met expression and EMT related molecules were evaluated using real-time PCR and immunohistochemistry in GC tissues. The role of HGF/c-Met pathway for EMT and anoikis was determined and c-Met TKI (SU11274) was tested for their ability to block HGF-induced biological effects in vitro and vivo. Results: In HGF(-)c-Met(+) GC cells,recombinant HGF promoted EMT phenotype characterized by morphology, impaired E-cadherin and induction of Vimentin. HGF promoted cell growth, invasiveness, migration ability and inhibition of anoikis. SU11274 blocked HGF-induced EMT and the biological effects in vitro. In contrast of HGF(+)c-Met(+) GC cells, HGF exposure was not affected biological outcome of EMT and anoikis but SU11274 blocked biological effect as same as in HGF(-)c-Met(+) GC cells. In vivo, HGF(+)c-Met(+) GC cell line only established PD and SU11274 intraperitoneally caused an inhibition of PD growth. Clinically, HGF expression was significantly positive correlated with c-Met expression in GC specimens. Increased HGF and c-Met demonstrated a significantly associated with poor prognosis and can predict PD, respectively. Furthermore, HGF was one of the independent factors for predicting PD. Immunohistochemical analysis showed HGF and c-Met were predominantly co-expressed in cancer cell of both primary GC and PD. Conclusions: We have demonstrated that HGF/c-Met pathway as an inducer of EMT and anoikis inhibition in GC cell. Co-expression of HGF and c-Met implicates its potential to promote PD in GC. Blocking the autocrine HGF/c-Met pathway may be clinically useful for the treatment of PD in GC. No significant financial relationships to disclose.