Endothelial Cell HIF-1α and HIF-2α Differentially Regulate Metastatic Success

• Published in: Cancer cell Vol. 21; no. 1; pp. 52 - 65
• Main Authors: Branco-Price, Cristina, Zhang, Na, Schnelle, Moritz, Evans, Colin, Katschinski, Dörthe M., Liao, Debbie, Ellies, Lesley, Johnson, Randall S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2012; Cell Press
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - physiology; Cell Hypoxia; Endothelial Cells - pathology; Feedback, Physiological; Female; Gene Deletion; Homeostasis; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Male; Mice; Neoplasm Metastasis; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - physiology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - physiology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2011.11.017

The hypoxia inducible transcription factors (HIFs) control many mediators of vascular response, including both angiogenic factors and small molecules such as nitric oxide (NO). In studying how endothelial HIF response itself affects metastasis, we found that loss of HIF-1α in endothelial cells reduces NO synthesis, retards tumor cell migration through endothelial layers, and restricts tumor cell metastasis, and that loss of HIF-2α has in each case the opposite effect. This results from differential regulation of NO homeostasis that in turn regulates vascular endothelial growth factor expression in an NO-dependent feedback loop. These opposing roles for the two HIF factors indicate that both they and endothelial cells regulate metastasis as malignancy progresses. ► Endothelial cell hypoxic response is a critical determinant of metastatic success ► HIF isoforms differentially regulate NO homeostasis in endothelium ► iNOS is essential for hypoxic NO production in endothelial cells ► HIF isoforms in endothelium differentially promote and hinder metastasis