Scientists have discovered how a protein called angiostatin may put the brakes on tumor growth in mice. Their findings, published in today's Proceedings of the National Academy of Sciences, could lead to a new class of cancer drugs.
In recent years the news media have trained a spotlight on angiostatin and its cousin endostatin, which appear to block cancer growth by stopping the birth of new blood vessels that nourish tumors. But little was known about how these promising proteins inhibit blood vessel formation. In search of a mechanism, Salvatore Pizzo and his colleagues at the Duke University Medical Center assumed that angiostatin doesn't work alone--that it must get help from some molecule on endothelial cells inside the blood vessels, whose growth is necessary for new vessel formation. The researchers went fishing for angiostatin-binding proteins in a preparation of endothelial cell membranes, and having found a possible candidate, shipped it to Peter Hojrup at Odense University in Denmark. Using mass spectrometry, Hojrup showed that the team had in fact found two proteins: the a and b subunits of adenosine triphosphate (ATP) synthase, an enzyme that manufactures the energy-rich molecule ATP.
That was a "shock," says Pizzo, because ATP synthase had not previously been found on the external membranes of higher cells. But by probing endothelial cells with antibodies to the enzyme's a subunit, Pizzo's group soon confirmed that the protein is present on the endothelial cell surface. The researchers also found that the antibodies decreased angiostatin binding to the cells by more than half, which in turn led to an 80% decrease in angiostatin's ability to inhibit endothelial cell growth.
Pizzo suspects that ATP synthase, perhaps by providing an extra source of ATP, plays a key role in the survival of endothelial cells, particularly in environments such as growing tumors, where oxygen concentrations are low. Therefore, if angiostatin does indeed work by inhibiting the ATP synthase, drug developers may start looking for molecules that do the same thing, but are less fragile than angiostatin, which has proven difficult to handle. "If I were a pharmaceutical company," says angiostatin's discoverer, Judah Folkman of Harvard Medical School, "that's what I would do."