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Angiogenesis

All cells need a constant source of oxygen and nutrients such as glucose (sugar). Our cells get their nutrients delivered to them via the blood. Nutrients and oxygen are pumped through the body via the circulatory system. When in the tissues, the nutrients cross the blood vessel walls and enter the spaces around the cells. Cells need nutrients constantly, and the process by which nutrients float over to cells takes time. In order to make sure that all cells get enough nutrients, our tissues are full of many small blood vessels (capillaries) that can deliver food to within a very short distance of any cell.

The development of blood vessels is an essential step in the growth of a tumor. Without vessels tumors cannot grow to be larger than a small fraction of an inch. The tumor cells produce (or cause nearby cells to produce) growth factors that stimulate the formation of blood vessels, as shown below.

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The growth of blood vessels into tumors is only half of the story. It was postulated as long ago as 1971 by Dr. Judah Folkman that prevention of angiogenesis could inhibit tumor growth by starving them of vital nutrients. The existence of natural inhibitors of angiogenesis was hinted at by an intriguing observation made by surgeons. They found that the surgical removal of a large primary tumor often lead to the rapid development of metastatic growths. This observation suggested that the primary tumor was producing something that kept small metastatic growths from progressing. When the large tumor was removed, the smaller tumors were free to grow.

The first naturally occuring inhibitor discovered was thrombospondin, identified in 1989 by Dr. Noel Bouck. Two more natural inhibitors were dicovered by Dr. Michael O'Reilly in Dr. Folkman's lab, angiostatin in 1994 and endostatin in 1997. These molecules are both small proteins that are derived from larger proteins that, remarkably, have different functions in the body. Clinical trials of endostatin for the treatment of cancer are currently underway.

The anti-angiogenesis treatments share two very exciting features: 1) Because they are natural products of the body, they should be much less toxic than conventional chemotherapy drugs. 2) Because they act on normal (blood vessel) cells instead of attacking the tumors directly, they should be much less likely to lead to the selection of drug-resistant tumors.

Since blood vessel formation, or the lack of it, is at the root of many human diseases, controlling this process has potential in several disorders in addition to cancer. The story of Judah Folkman's search was the subject of a NOVA special that can be viewed online.

Since this process is key to the growth of tumors, many drugs are currently being investigated for their potential to inhibit angiogenesis and tumor growth.
More on angiogenesis inhibitors.