Role of HIF-1, VEGF and FGF in tumor angiogenesis
Tumor angiogenesis is mediated by factors such as hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) . HIF-1 is a transcription factor that is upregulated in cancer cells and regulates oxygen homeostatsis in angiogenesis . Since tumors require high level of oxygen to maintain the abnormal vasculature and cell proliferation, HIF-1 increases in response to hypoxia and is responsible for many downstream targets that contribute to tumor angiogenesis, including various transporters and proteins like VEGF .
HIF-1β is constitutively expressed in cells and remains within the nucleus. HIF-1α translocates to the nucleus and evades proteasome degradation in hypoxic conditions. Under normoixc conditions, HIF prolyl 4-hydroxylases(PHDs) hydroxylate 2 proline residues (P402 and P564) on the oxygen-dependent degradation domain of HIF-1α to create docking sites for the E3 ubiquitin ligase, pVHL. Many other proteins, such as cullin 2 and RING-box protein 1, then bind to pVHL to form a complex in order to stabilize pVHL and facilitate pVHL's binding to HIF-1α's hydroxyl groups. The protein complex then ubiquitylates HIF-1α. Once polyubiquitinated, HIF-1α is recognized and degraded by the proteasome[9,10].
Under hypoxic conditions, HIF-1α is not degraded and stabilized, allowing the protein's concentration levels to rise. Without hydroxylation, HIF-1α is free to migrate into the nucleus and bind to HIF-1β. Along with transcriptional coactivators, p300 and cAMP response element-binding protein (CBP), the HIF heterodimer binds to the hypoxia-response elements(HRE) to induce transcription of genes to cope with hypoxia. Products produce from this transcription are involved in angiogenesis, erythropoiesis, glycolysis, and glucose transport; Tumours exploit these processes to promote cellular survival in hypoxic conditions. One of the few genes transcribed from HRE promoters are platelet-derived growth factor, transforming growth factor-α, and VEGF[9,10].
VEGF transcription is found to be upregulated in several human cancers including lung, breast, gastrointestinal tract, kidney, bladder, ovary, and endometrial carcinomas, intracranial tumors, glioblastomas, and capillary hemangioblastomas . This amplification in VEGF protein is linked to tumor vascularisation and the resulting increase of intratumoral microvessel density . These findings suggest that tumors produce and promote the production of VEGF in normal stromal cells. To confirm the role of VEGF in tumor neovascularisation, many studies have performed inihibition experiments, in which the findings demonstrate that when VEGF activity is inhibited in vivo, tumor angiogenesis and tumor growth vastly decrease . Similar to normal angiogenesis, VEGF-mediated tumor angiogenesis depends on hypoxia. The central necrotic tissue inside a tumor has low oxygen tension and selects for cells that are lacking apoptotic signals and thus, resistant to the damaging effects of hypoxia . As well, hypoxia can select for cells that induce VEGF production and angiogenesis in order to satisfy metabolic needs . In addition, VEGF increases vessel permeability, and with a lack of supportive cell types (e.g. pericytes), it induces the formation of ‘leaky’ blood vessels for neoplastic cells to disseminate from a primary tumor .
FGF is a transcription factor shown to induce endothelial cell proliferation and neovascularization in vivo . A soluble form of the basic FGF receptor is used in an inhibition study, and results indicate that tumor growth and vessel density decrease . bFGF has been shown to work in synergy with VEGF to stimulate vascularisation in vitro and in vivo . As well, FGF induces VEGF and VEGF receptor production .
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