A proangiognenic factor improves gamma-secretase inhibitor antitumoral effect in ovarian cancer xenografts

Abstract

Notch and PDGF systems are involved in angiogenic process in physiological and pathological conditions. Here, we developed tumours in nude mice injecting an epithelial ovarian tumour cell line. SKOV3 cells (1.106 cells in 100 μl) were inoculated subcutaneously into one flank of 6-10 week-old female nude mice. When the tumours were palpable, the mice were divided in three groups that received 1. Control, 2. DAPT (5mg/kg gamma-secretasa inhibitor), and 3. DAPT+PDGFB (0,1mg/kg). The treatments were administered during four consecutive days (day 1-4). At day 8, the animals were sacrificed and we determined: a. mice and tumour weight, b. tumour area, c. pericyte area and d. phosphor-AKT and PCNA (cell proliferation marker). Mice weight did not change between treatments. Tumour weight significantly decreased when PDGFB was co-administered with DAPT compared to Control group, but no differences were found between Control and DAPT treatments. Tumour area decreased with DAPT but not statistically different respect to Control. Interestingly, the cotreatment completely abolished the tumour growth, being the difference highly significant on days 7 and 8 post treatment. Similarly, the periendothelial area increased with PDGFB and DAPT administration. PCNA levels were significantly decreased in DAPT+PDGF group, but phosphorylated AKT did not change between groups. We conclude that PDGFB improves the antitumoral effect of gamma secretasa inhibitor, in part, recruiting periendothelial cells, stabilizing tumour vasculture, and thus, allowing the inhibitor to better reach the tumour and exert its antiproliferative effect.