Biooncology R-VEGF

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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-1α¹ HIF-1β¹
Oncogenes Tumor suppressor genes	Genes that stimulate or suppress tumor formation	c-Src oncogene² Bcr-Abl oncogene³ Ras oncogene^4-6 p53 tumor suppressor gene^7,8
Cellular receptors	Proteins on the cell surface that are part of signaling pathways	EGFR⁹ HER-2^10,11 IGF-IR^11,12
Other growth factors and cytokines	Proteins secreted by cells that stimulate cellular signaling	COX-2¹³ PDGF¹⁴

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).¹⁵

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.¹⁶

Hypoxia remains an important trigger of VEGF expression even after 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).^1,17 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.¹⁸

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:

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^19,20
Bcr-Abl is an oncogene formed from fusion of two proto-oncogenes, resulting in chronic myelogenous leukemia (CML).²¹ 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 expression³
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.^4-6
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. Genetic alteration of tumor suppressor genes, including p53, has been shown to induce VEGF production^7,8

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. Among other oncogenic effects, the EGFR signaling pathway results in increased VEGF production^9,22-24
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^10,25
Insulin-like growth factor 1 receptor (IGF-1R) activation: This receptor is associated with increased VEGF production in endometrial, pancreatic, and colorectal cancers^11,12

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 tumors^13,26-28
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.²⁹ 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 VEGF¹⁴

References:

1.: Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.
2.: Ellis LM, Staley CA, Liu W, et al. J Biol Chem. 1998;273:1052-1057.
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11.: Reinmuth N, Liu W, Fan F, et al. Clin Cancer Res. 2002;8:3259-3269.
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15.: Hellman S. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:265-289.
16.: Gimbrone MA Jr, Leapman SB, Cotran RS, et al. J Exp Med. 1972;136:261-276.
17.: Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3:401-410.
18.: Mizukami Y, Fujiki K, Duerr EM, et al. J Biol Chem. 2006;20:13957-13963.
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21.: Goldman JM, Melo JV. N Engl J Med. 2003;349:1451-1464.
22.: Arteaga CL. Oncologist. 2002;7(suppl 4):31-39.
23.: Salomon DS, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.
24.: Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol. 2001;2:127-137.
25.: Akagi M, Kawaguchi M, Liu W, et al. Br J Cancer. 2003;88:796-802.
26.: Yao M, Kargman S, Lam EC, et al. Cancer Res. 2003;63:586-592.
27.: Costa C, Soares R, Reis-Filho JS, et al. J Clin Pathol. 2002;55:429-434.
28.: Aoki T, Nagakawa Y, Tsuchida A, et al. Oncol Rep. 2002;9:761-765.
29.: Cao R, Brakenhielm E, Li X, et al. FASEB J. 2002;16:1575-1583.

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