ScienceVEGF

Environmental and cellular triggers of VEGF

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VEGF production and subsequent angiogenesis can be triggered by a number of factors, including both genes and gene products, in the cellular microenvironment.

 

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Hypoxia triggers VEGF expression

Without an independent blood supply, tumours must rely on diffusion to obtain oxygen and other nutrients, and typically cannot grow more than 2mm³ in size. Thus, a growing tumour without sufficient vasculature will have hypoxic areas (i.e. areas lacking in oxygen). In response to hypoxic conditions, tumours secrete VEGF in order to recruit new vasculature, which then provides a supply of oxygen.³²

 

Hypoxia remains an important trigger of VEGF expression even once a tumour becomes vascularised. As the tumour grows, it continually outgrows its existing blood supply, leaving a rim of necrotic and hypoxic tissue. The tumour responds by upregulating VEGF gene expression, primarily through the activity of HIF-1, a protein consisting of two subunits (HIF-1α and HIF-1β).^4,6 Recent research by Mizukami and colleagues (in colon cancer cells) suggests that an alternative mechanism for hypoxic induction of VEGF through a pathway involving PI3K and c-Myc may also play a role.³³

    

Oncogenes and tumour suppressor genes trigger VEGF expression

Oncogenes (genes that contribute to the production of a cancer) and tumour suppressor genes (genes encoding a protein that normally suppresses tumour formation) are associated with increased VEGF production. Oncogenes are generally mutated forms of proto-oncogenes (normal cellular genes capable of transforming a cell when activated). Some examples of oncogenes and tumour suppressor genes include

 

• c-Src is a proto-oncogene that appears to directly stimulate VEGF expression. c-Src signal transduction may also indirectly regulate VEGF expression through stimulation of additional factors.^17,34,35
• Bcr-Abl is an oncogene formed from fusion of two proto-oncogenes, resulting in CML.³⁶ A preclinical study in tumour cell lines showed that transfection of Bcr-Abl caused an increase in VEGF expression, whereas blocking the function of Bcr-Abl reduced VEGF expression.¹⁸
• Ras oncogene: Ras proteins are part of the signalling cascade of growth factor-induced angiogenesis. The genes that encode for Ras proteins have been associated with induction of VEGF expression in many solid tumours, including pancreatic, colorectal and non-small cell lung cancers.^19–21
• p53 tumour suppressor gene: Dysregulation of p53, normally a regulator of the cell cycle and trigger of apoptosis in damaged cells, has been implicated in the pathology of solid malignancies, including colorectal, breast and endometrial carcinomas. Genetic alteration of tumour suppressor genes, including p53, has been shown to induce VEGF production.^22,23

 

Cellular receptors trigger VEGF expression

Some receptors on the surface of cancer cells may induce increased expression of VEGF, including

 

• EGFR activation: also known as HER-1 and ErbB1, EGFR is expressed or overexpressed in a wide variety of common solid tumours, including breast, lung, colorectal, prostate, renal and ovarian cancers. Among other oncogenic effects, the EGFR signalling pathway results in increased VEGF production.^24,37–39
• HER-2 overexpression: also known as ErbB2, HER-2 has been associated with increased VEGF production in multiple solid tumour types.^25,26 In a study of 611 primary breast cancer patients, Konecny and colleagues demonstrated that HER-2/neu-positive tumours expressed significantly more VEGF than HER-2/neu-negative tumours.⁴⁰ Furthermore, overexpression of both HER-2/neu and VEGF was correlated with the poorest clinical outcome in the study.
• IGF-1R activation: this receptor is associated with increased VEGF production in breast, endometrial, pancreatic and colorectal cancers.^27,28

 

Other growth factors and cytokines trigger VEGF expression

VEGF, a growth factor and cytokine, may be produced in response to other growth factors and cytokines, including

 

• COX-2: the link between COX-2 overexpression and angiogenesis has been extensively documented. COX-2 has also been shown to mediate VEGF expression in numerous cell lines, but this effect is not evident in all tumours.^29,41–43
• PDGF: PDGF modulates angiogenesis in vivo by promoting endothelial cell survival and vascular maturation through the recruitment of pericytes and vascular smooth muscle cells.⁴⁴ Recent work by Ferrara et al. established a link between PDGF and recruitment of VEGF-producing stromal fibroblasts in a model deficient of tumour-derived VEGF.³⁰ The results suggest host-derived VEGF also plays an important role in angiogenesis, along with tumour-generated VEGF.