Abstract 1616: Survivin regulates endothelial cell proliferation, survival and angiogenesis.

Background - Survivin is a member of the inhibitor of apoptosis protein (IAP) family, and is reported to be overexpressed in a number of human cancers with high unmet medical need including breast, non-small-cell lung (NSCLC), colorectal, gastric, glioblastoma, and pancreatic cancers. Multiple studies have described survivin as a key regulator of tumour cell proliferation, survival and drug resistance, which has led to the advancement of survivin inhibitors, including antisense and small molecule drugs, and cancer vaccines, into clinical testing. In the tumour micro-environment, survivin overexpression has also been reported in tumour blood vessels and conditional deletion of survivin in endothelial cells results in murine embryonic lethality secondary to haemorrhage and defective vascular development. We therefore hypothesised that inhibition of survivin function in endothelial cells could have anti-angiogenic or vascular disruptive effects. Methods and Results - To better understand the role of survivin in primary endothelial cells we designed siRNAs capable of targeting multiple isoforms of human survivin. Using high content imaging assays we demonstrated that the siRNA were highly selective for survivin, inhibited the expression of multiple survivin splice variants, and had potent in vitro effects on endothelial cells. Survivin knockdown resulted in inhibition of cell cycle progression with the formation of enlarged, multi-nucleated cells, and in reduced endothelial cell survival. Survivin knockdown also impaired the formation of tube-like networks in vitro when co-cultured with human fibroblasts, but did not disrupt more established networks. Conclusion These data show an important role for survivin in primary endothelial cells, and suggest that targeted inhibition of survivin may have anti-angiogenic effects, but may not disrupt more established blood vessels. Citation Format: Cath Eberlein, Grace Opoku-Ansah, James Legg, Tim London, Frank Gebhardt, Gareth Davies, Natalie Tigue, Matthew McCourt, Julia White, Darren Cross, Ute Schaeper, Viia E. Valge-Archer. Survivin regulates endothelial cell proliferation, survival and angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2013-1616