Regulators of Vascular Endothelial Growth FactorA and Vascular Endothelial Growth Factor Receptor Expression

VEGF-A expression by tumor cells is upregulated by multiple stimuli, including cytokines, growth factors, hypoxia, and hypoglycemia in addition to activation of oncogenes and mutation of tumor suppressors. The mechanisms by which VEGF-A levels are induced by hypoxia have been extensively elaborated. In normoxic conditions the transcription factor HIF-1a is maintained at low levels, due to the action of the von Hippel-Lindau tumor suppressor (VHL) which directs its ubiquitinylation and proteosome mediated degradation. Hypoxia results in stabilization of HIF-1a, permitting activation of target genes that includes VEGF-A, as well as proteases and adhesion molecules.238,239 Many cancers are characterized by areas of hypoxia, and an association between hypoxia or HIF-1a levels in primary tumors and probability of metastasis has been clinically established.254 In agreement, experimental manipulation of VHL or HIF-1a activity is associated with changes in tumor growth, vascularization, and metastatic potential.255

Multiple studies have demonstrated that growth factor-mediated stimulation of tumor cells can lead to release of VEGF-A. In particular, activation of both EGFR and HER2 has been demonstrated to play a key role in breast, colon, and pancreatic tumor angiogenesis. Other growth factors that induce VEGF-A release, including IGF1 and hepatocyte growth factor (HGF), are frequently found to be overexpressed, together with their respective receptors, in tumors. VEGF-A upregulation occurs via both HIF-1a dependent and independent mechanisms and blockade of receptor activation is associated with decreased VEGF-A levels and compromised angiogenesis in experimental tumors.256

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