Abstract 3602: PTEN dependent angiogenesis is mainly regulated by (tumor secreted-) uPAR

Abstract

Abstract Tumor stroma crucially influences the growth of most epithelial tumors and is in focus of many therapeutic approaches. Several oncogenes and tumor suppressors coordinate complex signaling cascades in the tumor and its microenvironment. In this context, downregulation of the tumor suppressor PTEN was shown to be indispensable for (tumor-)angiogenesis and cancer outgrowth. However, the essential process leading to PTEN downregulation, favouring a pro-angiogenic phenotype, in tumor vasculature is unknown so far. Here we show that PTEN-dependent angiogenesis is centrally affected by tumor- secreted soluble uPAR. In detail, the presence of uPAR significantly influenced the levels of PTEN in vitro and in vivo. Endothelial cell stimulation with tumor- derived soluble uPAR remarkable decreased PTEN levels, which led to increased cell migration, enhanced wound healing as well as capillary-sprouting in vitro and enhanced endothelial cell invasion and functional vessel formation in a directed-in vivo angiogenesis assay. uPAR- derived PTEN regulation was not mediated via mRNA stability or decrease in PTEN degradation, but via regulation of PTEN transcription as revealed by actinomycin D experiments. uPAR thereby interacted with αv integrins, which enhanced FAK activation and - as a consequence - led to NFkB-dependent PTEN repression. Finally, the biological relevance of uPAR- dependent PTEN regulation was evaluated and confirmed via uPAR -/- crossbreds with either PTEN +/- or PTEN +/+ mice. Our results provide first evidence of the role of tumor-derived uPAR in regulation of the central phosphatase PTEN in angiogenic cell behaviour. Our findings give novel insights into the complex mechanism of the tumor- microenvironmental interaction and might lead to new therapeutic strategies in cancer. Citation Format: Matthias Unseld, Anastasia Chilla, Clemens Pausz, Johannes Breuss, Gernot Schabbauer, Gerald Prager. PTEN dependent angiogenesis is mainly regulated by (tumor secreted-) uPAR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3602. doi:10.1158/1538-7445.AM2014-3602