Endothelial hypoxic metabolism in carcinogenesis and dissemination : HIF-A isoforms are a NO metastatic phenomenon
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Cristina Branco-Price1, Colin E. Evans1, and Randall S. Johnson1
1 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Randall S. Johnson, email:
Keywords: Vascular endothelium, hypoxia, metastasis, HIF, HIF isoforms, nitric oxide, cell-specific responses
Received: October 2, 2013 Accepted: November 16, 2013 Published: November 18, 2013
Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression. Hypoxia is a broad stimulus that results in activation of hypoxia inducible factors (HIFs). Downstream HIF targets include angiogenic factors (e.g. vascular endothelial growth factor, VEGF) and highly reactive molecules (e.g. nitric oxide, NO) that act as cell-specific switches with unique spatial and temporal effects on cancer progression. The effect of cell-specific responses to hypoxia on tumour progression and spread, as well as potential therapeutic strategies to target metastatic disease, are currently under active investigation. Vascular endothelial remodelling events at tumour and metastatic sites are responsive to hypoxia, HIF activation, and NO signalling. Here, we describe the interactions between endothelial HIF and NO during tumor growth and spread, and outline the effects of endothelial HIF/NO signalling on cancer progression. In doing so, we attempt to identify areas of metastasis research that require attention, in order to ultimately facilitate the development of novel treatments that reduce or prevent tumour dissemination.
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