As a tumor suppressor protein that is mutated in more than half of all human cancers, p53 already seems to have more roles than an actor in a one-person play, with new responsibilities added to the list regularly. P53's known anticancer mechanisms include activating DNA repair proteins, inducing cell-cycle arrest and, if all else fails, inducing cell death. (See BioWorld Today, July 13, 2005, and July 14, 2005.)

Recent reports indicated that another tumor-fighting trick up p53's sleeve is the inhibition of angiogenesis, the new blood vessels that tumor cells need to survive and grow. In the Aug. 18, 2006, issue of Science, researchers from the University of Massachusetts Medical School in Worcester fleshed out the way in which p53 prevents angiogenesis: by influencing both collagen synthesis and breakdown, leading to a net increase of the antiangiogenesis factor endostatin.

"In order for small tumors to grow and become life-threatening, they need to vascularize," Jose Teodoro told BioWorld Today. "It's an absolutely necessary step."

Tumors, however, are in something of a tug-of-war with themselves: They secrete both pro- and antiangiogenic molecules. When p53 is lost, the tumor is no longer secreting factors such as endostatin that prevent it from vascularization. And this loss leads to a much more aggressive tumor.

The goal of the experiments was to determine just how p53 affects angiogenesis. The researchers began by screening for proteins that are more abundant in cells with high levels of p53, which is normally unstable and shows high levels only in response to cell damage. They found that p53 specifically activated the alpha-2 isoform of collagen prolyl hydroxylase; that enzyme is the bottleneck in collagen synthesis.

The scientists then tested whether the activation led to increased levels of collagen in cells with high levels of p53. To their surprise, the opposite turned out to be true. The reason being that p53 increased not only collagen synthesis, but also its breakdown. And one of the products of collagen breakdown is the antiangiogenic molecule endostatin.

The scientists confirmed the link between p53 and endostatin in several ways. Cells overexpressing either p53 or collagen prolyl hydroxylase had increased levels of endostatin, and p53's effects on endostatin could be blocked in cell culture by blocking the production of collagen prolyl hydroxylase in response to p53.

The researchers implanted tumor cells overexpressing collagen prolyl hydroxylase into immunosuppressed mice. The xenografts grew into tumors, but they, quite literally, were anemic. They were both smaller than control tumors and contained fewer blood vessels.

The results provide yet another reason why p53 is such an important tumor suppressor gene.

Angiogenesis research, or at least its public perception, has a colorful past. In the early days, "there was a lot of hype," Teodoro noted. But angiogenesis has remained an active area of research, and drying up tumor blood supply lines - though so far, not via endostatin or its analogues - has proved to be a successful approach. As has targeting VEGF, which is the major pro-angiogenic factor that tumors secrete.

Teodoro said that the success of targeting VEGF to date may be due to several reasons: "Aggressive tumors pump out a lot of VEGF, and it seems to be absolutely required for tumor vascularization," he said. "Some cancers produce antiangiogenic factors such as endostatin, but in the end, it is not enough to counter the effects of VEGF."

Also, "endostatin is only one in a growing list of angiogenesis inhibitors. Which antiangiogenesis inhibitor [or combination thereof] performs best in the clinic is still an open question."

At any rate, Genentech Inc.'s antiangiogenesis drug Avastin (bevacuzimab,) which targets VEGF, is approved for the treatment of colorectal cancer, and in 130 clinical trials for 25 different types of cancer, giving grounds for optimism beyond hype.

"Angiogenesis inhibitors by themselves are not a cure," Teodoro said. "But where they are used in combination with other agents, there's still a lot of promise."