Abstract 461: Identification of COX-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia: impact on angiogenesis and metastases

Abstract

Abstract Purpose: Cyclic hypoxia in tumors originates from heterogeneities in red blood cell flux and influences tumor cells but also endothelial cells lining tumor blood vessels. Whether pO2 fluctuations, in particular transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)-dependent gene program is largely unknown. Experimental design: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia vs continuous hypoxia to uncover a possible differential impact on angiogenesis and metastases. Results: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 since the observed increase in mRNA expression led to a significant increase in the expression and the activity of COX-2 (the protein product of PTGS2). HIF-1α was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction, as validated by the use of echinomycin and HIF-1α targeting siRNA. Using a specific COX-2 inhibitor and a dedicated COX-2-targeting siRNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of pre-challenged tumor cells. Conclusions: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO2, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 461.