FAK-ERK Activation In Cell/matrix Adhesion Induced By The Loss Of Apolipoprotein E Stimulates The Malignant Progression Of Ovarian Cancer

BackgroundOvarian cancer is the deadliest gynecological cancer.Because most patients do not have symptoms at early stages,over 70% of patients have their cancer detected at an advanced stage,which makes it harder to treat.Extracellular matrix(ECM)is a mediator of tumor progression.However,whether the alterations of the intraperitoneal ECM prior to tumor establishment affects the malignant progression of ovarian cancer remains elusive.ObjectiveTo investigate the extracellular matrix remodeling induced by the loss of apolipoprotein E and how this process affects the malignant progression of ovarian cancer.MethodsApolipoprotein(ApoE)knock-out mice was used to analyze the intraperitoneal ECM alterations by quantification of the major components of ECM.ID8 cells were implanted in vivo to generate allografts.uman ovarian cancer cell lines were characterized in vitro to assess the effects of ECM alterations on the malignant progression of ovarian cancer.Adhesion assay,immunochemistry,cytokines profile,proliferation assay,transwell invasion assay and western blot were used to determine the malignant phenotype of ovarian cancer cells.ResultsApoE loss induced increased ECM deposition,which stimulated the adhesions of ovarian cancer cells.The adhesion-mediated focal adhesion kinase(FAK)signaling enhanced the invasive behaviors of ovarian cancer cells through activation of a ERK-MMP linkage.This ECM-induced signaling cascade was further confirmed in human ovarian cancer cell lines in vitro.Furthermore,reversal of the ECM accumulation with BAPN or abrogation of adhesion-induced ERK activation in ovarian cancer cells with MEK inhibitors(MEKi)was found to effectively delay ovarian cancer progression.ConclusionsThese findings identify the FAK-ERK activation in cell/matrix adhesion in the malignant progression of ovarian cancer and the efficiency of BAPN or MEKi for tumor suppression,providing an impetus for further studies to explore the possibility of new anticancer therapeutic combinations.