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

Cristina Branco-Price,Na Zhang,Moritz Schnelle,Colin Evans,Dörthe M Katschinski,Debbie Liao,Lesley Ellies,Randall S Johnson

doi:10.1016/j.ccr.2011.11.017

Abstract

SummaryThe 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.

Highlights

There is a link between the metastatic process and oxygen deprivation (Brizel et al, 1996; Rofstad et al, 2010; Voss et al, 2011)
We have recently shown that in inflammatory cells, nitric oxide (NO) homeostasis is modulated by differential expression of the hypoxia inducible transcription factors (HIFs) isoforms HIF-1 and HIF-2 (Takeda et al, 2010) via regulation of two opposing uses of l-arginine: HIF-1a-induced expression of inducible nitric oxide synthase (iNOS), and HIF-2a induced expression of arginase 1 (ARG1), which can remove l-arginine from NO synthetic pathways and reduce NO levels
Loss of HIF-1a in Endothelial Cells Reduces Metastatic Rate To examine HIF function and endothelial hypoxic response in metastasis, metastatic success was assayed in murine progressive transgenic tumorigenesis, utilizing the MMTV-polyoma middle T (PyMT) model of mammary cancer (Lin et al, 2003)

Summary

Introduction

There is a link between the metastatic process and oxygen deprivation (Brizel et al, 1996; Rofstad et al, 2010; Voss et al, 2011). Significant evidence exists to indicate that migration of tumor cells during hematogenous metastasis is accelerated by a HIF-driven response (Liao et al, 2007; Lu et al, 2010; Zhong et al, 1999). This response in the metastatic cell may be driven in part by alterations in tumor oxygenation, which impacts the tumor endothelium, and it follows that the hypoxic endothelial cell (EC), because of its location, could act as a gatekeeper to metastatic cell intravasation

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