All cells, whether they are cancerous or not, need to be vascularized in order to receive the oxygen and nutrients required to support metabolic activity. Blood vessels also carry away metabolic waste products, such as carbon dioxide, which is expelled from the body by the lungs, and urea, expelled by the kidneys. The circulatory system, consisting of an extensive collection of arteries, veins, and capillaries, provides these essential services. Installing this system requires the formation of new blood vessels, a process that is called angiogenesis.
Angiogenesis is, of course, extremely important during embryogenesis, when the circulatory system is being formed, and during growth to adulthood. Vascularization during development is so efficient that virtually every cell in the body is less than 100 ^m away from the nearest capillary. Angiogenesis also has many important roles to play during adulthood, such as wound healing, formation of the corpus luteum after ovulation, formation of new endometrium after menstruation, and remodeling the vasculature of skeletal muscle after long periods of exercise.
There are many factors involved in the formation of blood vessels, but the best understood are a tyrosine kinase called vascular endothelial growth factor (VEGF) and a gene regulatory protein called hypoxia-inducible factor 1 (HIF-1). A shortage of oxygen in any cell of the body activates HIF-1, which, in turn, stimulates production and secretion of VEGF. The VEGF protein induces proliferation of endothelial cells (cells that make up blood vessels) that sprout from the nearest capillary and, following the VEGF concentration gradient, grow towards the hypoxic cells. Once the cells are vascularized and begin receiving an adequate oxygen supply, HIF-1 is inactivated and production ofVEGF drops off, thus terminating angiogenesis.
Tumors, like normal tissue, cannot grow to more than a millimeter or two in diameter without being vascularized. Consequently, angiogenesis is a prime target for cancer therapy. Clinical trials are currently in progress to test angiogenesis inhibitors on cancers of the breast, prostate, brain, pancreas, lung, stomach, ovary, and cervix, as well as leukemia and lymphomas. So far the studies have had limited success. Endostatin, a widely studied drug that is toxic to endothelial cells, showed great promise in preliminary studies. It is safe to administer, but it has failed to demonstrate antitumor effects. An extract from the Asian fruit Gleditsia sinensis (GSE) has been shown to be an effective blocker ofVEGF transcription but has yet to progress beyond the basic research stage. Another compound, extracted from green tea, called GTE is known to be a powerful blocker of endothelial cell proliferation but, like GSE, it is still at the preclinical stage of development. The most successful angiogenesis blocker tested so far is an anti-VEGF antibody called bevacizumab. This drug is being tested in phase I clinical trials, but it will be several years before this drug or any of the other known angiogenesis blockers are approved for routine medical use.
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