Data from Identification of Cyclooxygenase-2 as a Major Actor of the Transcriptomic Adaptation of Endothelial and Tumor Cells to Cyclic Hypoxia: Effect on Angiogenesis and Metastases

Abstract

<div>Abstract<p><b>Purpose:</b> Cyclic hypoxia in tumors originates from heterogeneities in RBC flux and influences not only tumor cells but also endothelial cells lining tumor blood vessels. Whether pO<sub>2</sub> fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)–dependent gene program is largely unknown.</p><p><b>Experimental Design:</b> We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia versus continuous hypoxia to uncover a possible differential effect on angiogenesis and metastases.</p><p><b>Results:</b> Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 because the observed increase in mRNA expression led to a significant increase in the expression and activity of cyclooxygenase-2 (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 small interfering RNA. Using a specific COX-2 inhibitor and a dedicated COX-2 targeting small interfering RNA, 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 prechallenged tumor cells.</p><p><b>Conclusions:</b> 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 pO<sub>2</sub>, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. Clin Cancer Res; 16(2); 410–9</p></div>