title: Ovarian cancer ascites enhance the migration of patient-derived peritoneal mesothelial cells via cMet pathway through HGF-dependent and -independent mechanisms.
abstract: Ovarian cancer ascites consist of a proinflammatory environment that is characterized by the presence of abundant human peritoneal mesothelial cells (HPMCs). Cytokines and growth factors in ascites modulate cell activities of tumor cells. The expression of proinflammatory cytokines in ascites is associated with a more aggressive tumor phenotype. The effect of ascites on HPMCs is for the most part unknown but this interplay is thought to be important for epithelial ovarian cancer (EOC) progression. Here, we examine the components of ascites, which stimulate patient-derived HPMC migration, from women with advanced EOC. We show that ovarian cancer ascites enhanced the migration of HPMCs. This effect was inhibited by heat treatment, hepatocyte growth factor (HGF) blocking antibodies and a HGF receptor (cMet) inhibitor. In ovarian cancer ascites, HGF is present at high concentration compared to benign fluids. Ascites-mediated activation of cMet was associated with Akt and EKR1/2 phosphorylation. This response was partly inhibited by heat treatment and cMet inhibitor. Ascites-induced migration and a cMet phosphorylation were strongly inhibited by epidermal growth factor receptor (EGFR) inhibitor PD153035, suggesting the transactivation of cMet by EGFR. Our study suggests that HGF and ligands of EGFR are factors that mediate ovarian cancer ascites-mediated migration of HPMCs by activating cMet and possibly downstream ERK1/2 and Akt pathways. The study provides evidence for the first time that ascites not only support tumor growth but also enhance the migratory potential of cancer-associated mesothelial cells, which in turn may support cancer progression.
authors.affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Matte
authors.affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Lane
authors.affiliation: Département de Pathologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Laplante
authors.affiliation: Département de Pathologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Perrine
authors.initials: P
authors.lastname: Garde-Granger
authors.affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Claudine
authors.initials: C
authors.lastname: Rancourt
authors.affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Piché
mesh_terms: D001201:Ascites / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010529:Peritoneal Cavity / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
chemical_list: C558663:2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol; D016207:Cytokines; D018836:Inflammation Mediators; D011719:Pyrazines; D014230:Triazoles; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Akt; ERK1/2; ascites; cMet; hepatocyte growth factor; mesothelial cells; ovarian cancer