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

CAMILA PAZOS, GONZALO SEQUEIRA, DALHIA ABRAMOVICH, FERNANDA PARBORELL, MARTA TESONE AND GRISELDA IRUSTA.

Newport

Workshop; Gordon Conferences; 2013

Gordon Conferences

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 PDGFB. 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 some angiogenic factors like PDGFD and PDGF receptor Beta, and Angiopoyetin 1 and TIE2 receptor. However, no PDGFB 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 is 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 PDGFB. With the observed results we conclude that ovarian granulosa tumor cells produce angiogenic factors to stimulate and stabilize tumor vasculature to cooperate with the growth and dissemination of the tumor cells. Moreover, in ovarian epithelial cancer model, PDGFB could be acting as an adjuvant drug to facilitate gamma-secretase inhibitor action on tumor growth