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Hypoxic tumor environment promotes angiogenesis¹

Molecular mechanisms of hypoxia-induced angiogenesis¹

Molecular mechanisms of hypoxia-induced angiogenesis. Under normoxic conditions (panel A), HIF-1α is hydroxylated by the active prolyl-4-hydroxylase enzyme, which facilitates the binding of VHL protein and leads to rapid HIF-1α degradation by the ubiquitin proteasome system. In the face of hypoxia (panel B), the hydroxylase enzyme is inactive and HIF-1α is stabilized in its de-hydroxylated state. The stable HIF-1α translocates to the nucleus, where it accumulates and dimerizes with the constitutively expressed HIF-1β, forming the intact HIF-1 complex. This complex binds hypoxia response elements (HREs) in selective genes to alter transcriptional activity. A notable hypoxia-induced gene is that coding for vascular endothelial growth factor (VEGF), a cytokine which potently stimulates neoangiogenesis.

Mol Cancer. 2003;2:1-10. ©2003 licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. http://www.molecular-cancer.com/content/2/1/12.

Growing at an accelerated rate, tumor cells exhaust the oxygen supply, resulting in a microenvironment that induces a hypoxic drive. Median tissue pO₂ levels in pancreatic carcinoma have been recorded as low as 0 to 5.3 mm Hg, and median pO₂ levels <2.5 mm Hg were found in 24% to 95% of specimens. In contrast, adjacent areas of normal pancreatic tissue had median pO₂ levels of 24.3 to 92.7 mm Hg, with ≤9% having levels <2.5 mm Hg.¹

Low tissue pO₂ levels promote hypoxia inducible factor (HIF-1) signaling for gene transcription of VEGF mRNA, causing the release of VEGF from tumor cells. The growth of tumor cells and their blood supply is thus driven by hypoxia-induced release of VEGF from the very tumor cells that express VEGF receptors.² These elements form the basis of an autocrine growth cycle in which VEGF and its receptors act to sustain tumor growth.³

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Koong AC, Mehta VK, Le QT, et al. Int J Radiat Oncol Biol Phys. 2000;48:919-922.

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Duffy JP, Eibl G, Reber HA, et al. Mol Cancer. 2003;2:1-10.

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Büchler P, Reber HA, Büchler MW, et al. Ann Surg. 2002;236:738-749.