CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells

The tumour microenvironment is a highly heterogeneous entity that plays crucial roles in cancer progression. As the most prominent stromal cell types, cancer-associated fibroblasts (CAFs) produce a variety of factors into the tumour microenvironment. In the present study, we firstly isolated CAFs from tumour tissues of the patients with ovarian cancer and demonstrated that the hepatocyte growth factor (HGF) was highly expressed in the supernatants of CAFs. CAF-derived HGF or human recombinant HGF promoted cell proliferation in human ovarian cell lines SKOV3 and HO-8910 cells. Western blotting analysis also showed that CAF-derived HGF or recombinant HGF activated c-Met/phosphoinositide 3-kinase (PI3K)/Akt and glucose-regulated protein 78 (GRP78) signalling pathways in ovarian cancer cells, and these effects could be abrogated by anti-HGF and c-Met inhibitor INCB28060. Moreover, HGF in CAF matrix attenuated paclitaxel (PAC)-caused inhibition of cell proliferation and increase in cell apoptosis through activating c-Met/PI3K/Akt and GRP78 pathways in SKOV3 and HO-8910 cells. The results in vitro were further validated in nude mice. These findings suggest that CAF-derived HGF plays crucial roles in cell proliferation and drug resistance in ovarian cancer cells.