The endothelial-like cell phenotype of ovarian granulosa tumor cells and gamma-secretase inhibition in a mouse model of ovarian epithelial cancer

PAZOS CAMILA; SEQUEIRA GONZALO; ABRAMOVICH DALHIA; PARBORELL FERNANDA; TESONE MARTA; IRUSTA GRISELDA

New Port, RI

Congreso; Gordon Research Conferences: Angiogenesis; 2013

Many studies have associated cancer aggressiveness with a high degree of cellular plasticity. This seems to have implications with respect to the efficacy of angiogenesis inhibitors. Our objectives were: 1) To analyze the expression of some angiogenic factors in an ovarian granulosa tumor cell line (KGN) by western blot, 2) To evaluate KGN cell migration in the presence of a gamma secretase inhibitor (DAPT) and 3) To determine the tumor growth in a mouse xenograft model of epithelial ovarian cancer in the presence of DAPT or DAPT+ recombinant PDGF-BB (Platelet-Derived Growth Factor BB). For this latter objective, SKOV3 cells were injected subcutaneously in nude mice and when tumors were detectable, drugs were administered intravenously for four consecutive days. In protein extracts of KGN cells, we observed that these cells express angiogenic factors like PDGF-DD , its membrane receptor, PDGFR Beta, ANGPT-1 (Angiopoyetin-1) and its membrane receptor, TIE2. However, no PDGF-BB was detected in this cell line. KGN cells also express some of the Notch system members like the ligands JAGGED1 and DLL4, and the receptors NOTCH1 and NOTCH4. These cells secrete the main angiogenic factor VEGF and the inhibition of the Notch system increased its levels. We also analyzed cell migration of KGN cells in the presence of DAPT inhibitor which was decreased compared to control conditions.   In the mouse xenograft model of epithelial ovarian cancer using SKOV3 cell line, tumor size of DAPT group was decreased compared to tumor size of the control group though there is no statistical significant difference between them. However, we observed a significant inhibition of tumor size when the inhibitor DAPT was co-administered with recombinant PDGF-BB molecule. Based in these findings, we conclude that ovarian granulosa tumor cells produce angiogenic factors that may  stabilize tumor vasculature to cooperate with the growth and dissemination of the tumor cells. Moreover, in ovarian epithelial cancer model, PDGF-BB could be acting as an adjuvant drug to facilitate gamma-secretase inhibitor action on tumor growth.