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The Molecular Perspective: VEGF and Angiogenesis

David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell

Our cells need a constant supply of oxygen to power their diverse molecular processes. This oxygen is delivered by the blood, so nearly all of our cells are within a tenth of a millimeter from a blood capillary. Tumor cells are no exception. If a collection of cancerous cells grows much larger than a millimeter, it will starve itself of oxygen and energy unless new blood vessels are built to provide a supply. For this reason, many cancer cells co-opt the normal processes of angiogenesis, the development of blood vessels, in order to build their own blood supply.

Vascular endothelial growth factor, or VEGF (shown in Fig. 1), is the key signal used by oxygen-hungry cells to promote growth of blood vessels. It binds to specialized receptors on the surfaces of endothelial cells (shown in Fig. 2) and directs them to build new vessels. After receiving this message, the cells build specialized proteases to break through the basal lamina, and migrate into the oxygen-starved region. Once there, the cells multiply and form into tubes, creating a new path for blood to flow.

View larger version (55K): [in this window] [in a new window]   Figure 1. VEGF and antibodies. Antibodies against VEGF have been shown to block binding to the VEGF receptors, and thus may be used to inhibit the growth of new blood vessels. In this illustration, VEGF is at the center, in red and purple, with two antibodies bound at top and bottom, in yellow and orange. VEGF is composed of two identical subunits. The core at the center forms the dimer and is involved in binding to the receptor. The small domains extending from the core of VEGF, which are built with different sizes in several subforms of VEGF, bind to heparin and to carbohydrates on the cell surface, modulating the activity of VEGF. Coordinates were taken from entries 1bj1, 2vgh, and 1hzh at the Protein Data Bank (http://www.pdb.org).

View larger version (109K): [in this window] [in a new window]   Figure 2. VEGF in action. VEGF, shown in red, binds to receptors, shown in yellow, on the surface of endothelial cells. The portion of receptor inside the cell is a tyrosine kinase enzyme, and the portion outside the cell binds to VEGF. VEGF brings together two receptors, so that inside the cell, the two kinase regions are close enough to add phosphate groups to each other. These phosphate groups are then recognized by the signaling apparatus inside the cell, beginning the process of angiogenesis.

As you can imagine, this is an attractive process for the design of cancer therapy. By selectively inhibiting the growth of new blood vessels, we can starve tumor cells. Effective methods have been developed to do just this, using drugs or antibodies to block the formation of VEGF or the binding of VEGF to its receptors. Researchers have found, however, that these methods are effective for stopping the growth of a tumor, but generally not for reducing the size of an existing tumor. They are powerful tools, however, when used in combination with agents that attack other key points in the tumor cell.

FURTHER READING

Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1996;1:27–31.

Saaristo A, Karpanen T, Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene 2000;19:6122–6129.[CrossRef][Medline]

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.[CrossRef][Medline]

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