Abstract C3: Tumor-derived soluble uPAR regulates tumor angiogenesis via PTEN.

Abstract

Abstract The urokinase receptor uPAR (CD87), a GPI-anchored protein, is frequently over-expressed in tumor cells. uPAR provokes numerous cellular functions by focusing proteolytic activity on the cell surface, but also by inducing intracellular signal transduction via transmembrane interaction partners, thus inducing cell migration and invasion as well as cell survival. Soluble tumor-derived uPAR has recently been described to activate endothelial cells and was suggested to promote angiogenesis. Consistently, high uPAR expression in tumor cells or high serum levels of circulating uPAR predict worse prognosis of breast, lung or colorectal cancer patients. In this study, we found that tumor-derived soluble uPAR is a key regulator of PTEN expression in endothelial cells. HEK cells deficient in endogenous uPAR or uPAR deficient endothelial cells derived from uPAR -/- mice had high PTEN mRNA as well as protein levels, while reconstitution of endogenous as well as addition of soluble exogenous uPAR decreased PTEN levels. uPAR, thereby, led to an integrin-dependent activation of the NFkB pathway, a known transcription pathway inhibitor of PTEN. As a consequence of PTEN downregulation, the downstream PKB/Akt signalling pathway became activated, which led to an enhanced migratory as well as cell survival activity in endothelial cells. Cross-breeding of uPAR -/- mice with endothelial cell-specific PTEN +/- mice, thereby led to a rescue of the high migratory phenotype of PTEN heterozygous endothelial cells in vitro and angiogenesis formation in a directed in vivo angiogenesis assay (DIVAA). From our date we conclude that tumor-derived uPAR is a major regulator of PTEN expression in endothelial cells, which leads to the induction of the PI3K/Akt-pathway and an enhanced angiogenic phenotype. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C3. Citation Format: Gerald W. Prager, Matthias Unseld, Marina Poettler, Christoph Zielinski. Tumor-derived soluble uPAR regulates tumor angiogenesis via PTEN. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C3.