Call of the tumor: chemical trigger for blood vessel growth.

New tissue--whether it results from repair, normal growth or malignancy -- demands a blood supply. Fifteen years ago, a scientist proposed that tumors disperse potent chemical factors that cause nearby blood vessels to sprout and extend. In a series of articles in the Sept. 24 BIOCHEMISTRY, Bert L. Vallee and his colleagues at Harvard Medical School in Boston report the identification, purification and detailed characterization of a human protein that triggers extension of the blood vessel system. These papers provide the first report on work over more than a decade.

The identification of such an angiogenic factor has widespread implications for treatment of diseases. Such a factor may lead to therapies to increase blood supply in cases of heart disease, stroke, fetal blood insufficiency and wound healing. Conversely, other therapies may inactivate the angiogenic factor to decrease blood supply to solid tumors and to treat rheumatoid arthritis, diabetic symptoms and skin disorders.

The chemical is a small protein derived from a human colon tumor. Very small amounts of the protein, which the researchers call angiogenin, generate blood vessel growth in living tissue of various animal species, including chick, rabbit and mouse. While the scientists have not detected angiogenin produced by any non-malignant tissue, they do find its gene in normal cells.

A surprising aspect of angiogenin is that its amino acid sequence has similarities to that of another human protein, an enzyme that breaks up RNA. James F. Riordan, who works with Vallee, says, "This finding may give some clues to angiogenin's mode of action and it may help us design an inhibitor of angiogenin." So far, no enzymatic activity of angiogenin has been found.

While Vallee kept his work on angiogenin under wraps, other scientists have described other blood-vessel stimulating chemicals. The originator of the angiogenesis hypothesis, Judah Folkman, also at Harvard Medical School, and others have reported a set of proteins that trigger growth of blood vessels and also the division of certain cells in laboratory culture. These protein are characterized by an unusually strong binding to a sugar polymer, heparin. Roger Guillemin and colleagues at the Salk Institute in San Diego will soom publish the amino acid sequence of one called fibroblast growth factor.

"Vallee's factor is a completely different molecule," says Michael Klagsbrun, a colleague of Folkman's. "It doesn't stimulate [cell] proliferation and it does not bind heparin. So there are at least two classes of angiogenesis factors."

But Vallee is unwilling to regard the heparin-binding molecules at true angiogenesis factors. "The ancillary activity confuses the issue," he says, adding that angiogenin is 1,000 times as potent in triggering blood vessel growth as is the fibroblast growth factor. The work of both Folkman and Vallee has been funded by a 12-year, $25 million agreement with Monsanto Co. in St. Louis, Mo.

Valleehs major interest is not the therapeutic applications of angiogenin, but the basic question of how the growth and development of biological systems is turned on and off. "The question is how one comes to the point of inducing or organizing a system by molecular entities. Extension [of blood vessels] is as much a problem in organization and development in an embryo," Vallee says, "Generation of organs has been the stuff of scientific dreams for decades. It is now a reality.