HIF in vascular development and tumour angiogenesis

Hypoxia stimulates angiogenesis through the up-regulation of vascular endothelial growth factor and other angiogenic cytokines. Members of the hypoxia-inducible factor (HIF) family of transcription factors play a central role in the cellular hypoxia response. To address the function of HIF signallin...

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Bibliographic Details
Published in:	Novartis Foundation symposium Vol. 283; p. 126
Main Authors:	Breier, Georg, Licht, Alexander H, Nicolaus, Anke, Klotzsche, Anne, Wielockx, Ben, Kirsnerova, Zuzana
Format:	Journal Article
Language:	English
Published:	England 2007
Subjects:	Animals Blood Vessels - embryology Cardiovascular System - embryology Endothelial Cells - enzymology Endothelial Cells - metabolism Hypoxia-Inducible Factor 1 - chemistry Hypoxia-Inducible Factor 1 - metabolism Mice Neoplasms - blood supply Neoplasms - metabolism Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - therapy Receptors, Vascular Endothelial Growth Factor - metabolism
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Summary:	Hypoxia stimulates angiogenesis through the up-regulation of vascular endothelial growth factor and other angiogenic cytokines. Members of the hypoxia-inducible factor (HIF) family of transcription factors play a central role in the cellular hypoxia response. To address the function of HIF signalling in physiological and pathological angiogenesis, we used a dominant-negative approach that interferes with the function of both HIF-1 and HIF-2. The expression of a dominant-negative HIF mutant in endothelial cells inhibited endothelial sprouting and disrupted cardiovascular development in mouse embryos, demonstrating that endothelial HIF function is essential for embryogenesis. However, the inhibition of HIF activity in tumour vessels accelerated the growth of experimental fibrosarcoma and osteosarcoma. The over-expression of prolyl hydroxylase domain protein 2 (PHD2), an enzyme that negatively regulates HIF stability, strongly reduced growth of LM8 osteosarcoma cells in vivo. Our results are in line with the complexity of HIF function and indicate that HIF inhibition might not be an ideal anti-tumour strategy.
ISSN:	1528-2511