Data from Loss of Fibroblast HIF-1α Accelerates Tumorigenesis

Abstract

<div>Abstract<p>Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including <i>VHL</i>, <i>HIF-1α</i>, <i>HIF-2α</i>, and <i>VEGF-A</i>, were knocked out specifically in tumor stromal fibroblasts. We found that loss of <i>HIF-1α</i> and its target gene <i>VEGF-A</i> accelerated tumor growth in murine model of mammary cancer. <i>HIF-1α</i> and <i>VEGF-A</i> loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast <i>HIF-1α</i> response is a critical component of tumor vascularization. <i>Cancer Res; 72(13); 3187–95. ©2012 AACR</i>.</p></div>