Environmental & cellular triggers of VEGF
Vascular endothelial growth factor (VEGF) production and subsequent angiogenesis can be triggered by a number of factors, including both genes and gene products, in the cellular microenvironment. To learn more about individual stimuli, click on the links in the table below.
| VEGF Triggers | Description/Affect | Factors Involved |
| Hypoxia | Lack of oxygen in the tumor microenvironment | HIF-1α4
HIF-1β4 |
Oncogenes
Tumor suppressor genes | Genes that stimulate or suppress tumor formation | c-Src oncogene14
Bcr-Abl oncogene15
Ras oncogene16-18
p53 tumor suppressor gene19,20 |
| Cellular receptors | Proteins on the cell surface that are part of signaling pathways | EGFR21
HER-222,23
IGF-IR23,24 |
| Other growth factors and cytokines | Proteins secreted by cells that stimulate cellular signaling | COX-226
PDGF27 |
Hypoxia triggers VEGF expression
Hypoxia in tumor cells
This image illustrates hypoxic conditions in a tumor: cells closest to vasculature have a sufficient supply of oxygen, whereas oxygen supply diminishes further from blood vessels. As the oxygen supply decreases, cells become hypoxic (light purple areas) and later necrotic (gray areas).28
DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 2001. Used by permission of Lippincott Williams & Wilkins.
Without an independent blood supply, tumors must rely on diffusion to obtain oxygen and other nutrients, and typically cannot grow more than 2 mm3 in size. Thus, a growing tumor without sufficient vasculature will have hypoxic—that is, lacking in oxygen—areas. In response to hypoxic conditions, tumors secrete vascular endothelial growth factor (VEGF) in order to recruit new vasculature, which then provides a supply of oxygen.29
Hypoxia remains an important trigger of VEGF expression even once a tumor becomes vascularized. As the tumor grows, it continually outgrows its existing blood supply, leaving a rim of necrotic and hypoxic tissue. The tumor responds by upregulating VEGF gene expression, primarily through the activity of hypoxia inducible factor-1 (HIF-1), a protein consisting of 2 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.30
Oncogenes and tumor suppressor genes trigger VEGF expression
Oncogenes (genes that contribute to the production of a cancer) and tumor suppressor genes (genes encoding a protein that normally suppresses tumor formation) are associated with increased vascular endothelial growth factor (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 tumor suppressor genes include:
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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 factors11,31
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Bcr-Abl is an oncogene formed from fusion of two proto-oncogenes, resulting in chronic myelogenous leukemia (CML).32 A preclinical study in tumor cell lines showed that transfection of Bcr-Abl caused an increase in VEGF expression, whereas blocking the function of Bcr-Abl reduced VEGF expression15
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Ras oncogene: Ras proteins are part of the signaling cascade of growth factor—induced angiogenesis. The genes that encode for Ras proteins have been associated with induction of VEGF expression in many solid tumors, including pancreatic, colorectal, and non-small cell lung cancers16-18
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p53 tumor 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 tumor suppressor genes, including p53, has been shown to induce VEGF production19,20
Cellular receptors trigger VEGF expression
Some receptors on the surface of cancer cells may induce increased expression of vascular endothelial growth factor (VEGF), including:
- Epidermal growth factor receptor (EGFR) activation: Also known as HER-1 and ErbB1, EGFR is expressed or overexpressed in a wide variety of common solid tumors, including breast, lung, colorectal, prostate, renal, and ovarian cancers. Among other oncogenic effects, the EGFR signaling pathway results in increased VEGF production21,33-35
- Human epidermal receptor-2 (HER-2) overexpression: Also known as ErbB2, HER-2 has been associated with increased VEGF production in multiple solid tumor types.22,23,36 In a study of 611 primary breast cancer patients, Konecny and colleagues demonstrated that HER-2/neu—positive tumors expressed significantly more VEGF than HER-2/neu—negative tumors. Furthermore, overexpression of both HER-2/neu and VEGF was correlated with the poorest clinical outcome in the study37
- Insulin-like growth factor 1 receptor (IGF-1R) activation: This receptor is associated with increased VEGF production in breast, endometrial, pancreatic, and colorectal cancers24,25
Other growth factors and cytokines trigger VEGF expression
Vascular endothelial growth factor (VEGF), a growth factor and cytokine, may be produced in response to other growth factors and cytokines, including
- Cyclooxygenase-2 (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 tumors26,38-40
- Platelet-derived growth factor (PDGF): PDGF modulates angiogenesis in vivo by promoting endothelial cell survival and vascular maturation through the recruitment of pericytes and vascular smooth muscle cells.41 Recent work by Ferrara et al established a link between PDGF and recruitment of VEGF-producing stromal fibroblasts in a model deficient of tumor-derived VEGF. The results suggest host-derived VEGF also plays an important role in angiogenesis, along with tumor-generated VEGF27
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