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.

[1]  E. Lengyel,et al.  Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra‐cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum , 2007, International journal of cancer.

[2]  Robert A. Weinberg,et al.  Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type , 2006, Cell cycle.

[3]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[4]  Hui Zhou,et al.  Novel Mechanism of Anti-apoptotic Function of 78-kDa Glucose-regulated Protein (GRP78) , 2011, The Journal of Biological Chemistry.

[5]  E. Rosen,et al.  Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum , 2006, Anti-cancer drugs.

[6]  D. Egan,et al.  Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78. , 2005, Cancer research.

[7]  Li Meng,et al.  Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. , 2016, International journal of oncology.

[8]  G. Cooper,et al.  Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. , 1995, Science.

[9]  David E. Misek,et al.  Global Profiling of the Cell Surface Proteome of Cancer Cells Uncovers an Abundance of Proteins with Chaperone Function* , 2003, The Journal of Biological Chemistry.

[10]  Y. DeClerck,et al.  Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. , 2013, Cancer research.

[11]  J. Dungan,et al.  Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer , 2011 .

[12]  Li Ying,et al.  Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform , 2015, PloS one.

[13]  Y. Sekido,et al.  Hepatocyte Growth Factor Reduces Susceptibility to an Irreversible Epidermal Growth Factor Receptor Inhibitor in EGFR-T790M Mutant Lung Cancer , 2009, Clinical Cancer Research.

[14]  B. Teh,et al.  Genetic and expression profiles of squamous cell carcinoma of the head and neck correlate with cisplatin sensitivity and resistance in cell lines and patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  S. Ha,et al.  The Prognostic Significance of Cancer-Associated Fibroblasts in Esophageal Squamous Cell Carcinoma , 2014, PloS one.

[16]  E. Kistner,et al.  c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. , 2007, Cancer research.

[17]  Amy S. Lee,et al.  Glucose regulated proteins in cancer progression, Drug resistance and immunotherapy , 2006, Cancer biology & therapy.

[18]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[19]  A. Tomida,et al.  Glucose‐regulated protein 78: A new partner of p53 in trophoblast , 2009, Proteomics.

[20]  M. Augsten.  Cancer-Associated Fibroblasts as Another Polarized Cell Type of the Tumor Microenvironment , 2014, Front. Oncol..

[21]  Kim Moran-Jones.  The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer , 2016, Molecular Diagnosis & Therapy.

[22]  P. Scherle,et al.  Targeting the c-MET signaling pathway for cancer therapy. , 2008, Expert opinion on investigational drugs.

[23]  Kristina Stumpf,et al.  Tumor-associated stromal cells as key contributors to the tumor microenvironment , 2016, Breast Cancer Research.

[24]  Qi Wang,et al.  Functional Investigation of NCI-H460-Inducible Myofibroblasts on the Chemoresistance to VP-16 with a Microfluidic 3D Co-Culture Device , 2013, PloS one.

[25]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[26]  S. Fang,et al.  Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer , 2007, Clinical & Experimental Metastasis.

[27]  A. Godwin,et al.  Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer , 2017, Reproductive Sciences.

[28]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[29]  Bing-Hua Jiang,et al.  Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. , 2006, Cellular signalling.