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.
['Deying|Wei|W|', 'Feng|Geng|G|', 'Shumei|Liang|L|', 'Hui|Zhao|Z|', 'Ming|Liu|L|', 'Hongqing|Wang|W|']
D000818:Animals D015153:Blotting, Western D000072645:Cancer-Associated Fibroblasts D045744:Cell Line, Tumor D049109:Cell Proliferation D019008:Drug Resistance, Neoplasm D000091342:Endoplasmic Reticulum Chaperone BiP D005260:Female D006360:Heat-Shock Proteins D017228:Hepatocyte Growth Factor D006801:Humans D008807:Mice, Inbred BALB C D008819:Mice, Nude D008856:Microscopy, Fluorescence D010051:Ovarian Neoplasms D019869:Phosphatidylinositol 3-Kinases D051057:Proto-Oncogene Proteins c-akt D019859:Proto-Oncogene Proteins c-met D011994:Recombinant Proteins D015398:Signal Transduction D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
cell proliferation drug resistance ovarian cancer cancer-associated fibroblasts hepatocyte growth factor