A detailed look at the VEGF pathway

The VEGF ligand plays a central role in angiogenesis throughout tumor development

The production of VEGF is stimulated by upstream activators, including environmental cues, growth factors, oncogenes, cytokines, and hormones. The binding of VEGF to its receptors on the surface of endothelial cells activates intracellular tyrosine kinases, triggering multiple downstream signals that promote angiogenesis. Although there are multiple variants of both the VEGF ligand and its receptor, the angiogenic effects of this pathway are primarily mediated through the interaction of VEGF-A (the most common variant, often referred to simply as VEGF) with VEGFR-2. Other non-VEGF factors are thought to play a secondary role in angiogenesis, though many of these factors may also impact additional nonangiogenic pathways.^1-4

The VEGF ligand: at the center of the angiogenic pathway^1,2

1. Upstream activators stimulate the production of VEGF
2. VEGF binds to receptors on endothelial cells
3. Angiogenesis is mediated primarily through the interaction of VEGF-A with VEGFR-2
4. Other variants of the VEGF ligand and receptor play a secondary role in this process

More specifically, a number of interrelated signals and processes have been identified that lead to the production of VEGF and, subsequently, to neovascularization of a tumor. The pages that follow provide a detailed explanation of the various steps in the VEGF pathway.

• VEGF is produced in response to a variety of environmental and cellular stimuli
• An imbalance between pro- and anti-angiogenic factors can turn on the “angiogenic switch”
• VEGF ligands bind to the VEGFR family of receptors
• Receptor binding initiates a downstream signaling cascade

To go directly to a particular section of the pathway, click on the links below.

References:

1.

Ferrara N. Endocr Rev. 2004;25:581-611.

2.

Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.

3.

Ferrara N, Hillan KJ, Gerber HP, Novotny W. Nat Rev Drug Discov. 2004;3:391-400.

4.

Baka S, Clamp AR, Jayson GC. Expert Opin Ther Targets. 2006;10:
867-876.