Nov. 15, 2001 A small protein released by cancer cells can inhibit the growth of secondary tumors in mice and could be used to design new types of anti-cancer drugs, according to Canadian researchers. The finding was published in the Oct. 30 edition of Biochemistry, a peer-reviewed journal of the American Chemical Society, the world’s largest scientific society.
A cancer is most deadly when it spreads to multiple organs, a process called metastasis. But doctors who find a malignant tumor that seems to be limited to one organ cannot simply cut it out because doing so often means secondary tumors start to grow rapidly. In studies with mice, David Waisman, Ph.D., a professor at the University of Calgary, showed that the p22 protein prevents secondary tumors from growing after the primary tumor is removed. He believes it acts by inhibiting blood vessel growth, which is essential for tumor development.
“We might be able to use p22 as a drug itself. Or we could design drugs based on it that would be even more potent,” said Waisman. Although several drugs to limit metastasis are already on the market, none are ideal, he added, and p22 offers several advantages.
The molecule is unlikely to cause an immune response because it is a fragment of plasminogen, a protein found in the blood under normal conditions. P22 itself may be found in healthy people, although that possibility is as yet unproven.
Or, doctors could take advantage of the fact that p22 targets only those cells that help tumors grow. “If we could figure out a way to tether a cytotoxic”—cell-killing—“agent to p22, we would have a very efficient method of stopping tumors,” said Waisman. The small size of p22 means it would probably be cleared from the bloodstream quickly, reducing the chance of side effects, he added.
So far, p22 has not been tested on people and any treatments would not be available for years.
Waisman’s group studied more than 50 mice. The scientists induced cancer in the mice’s necks, then removed the tumors two weeks later, using the methods a surgeon would use to remove a tumor from a human. Half the mice then received daily p22 injections; half received a placebo. Two weeks later, the scientists weighed the mice’s lungs. The placebo group’s lungs weighed more than three times as much as the p22 group’s. The extra weight was due to cancerous growths, they said.
The researchers showed that p22 is a natural compound released by cancerous cells themselves to control blood vessel growth. Cancer cells must force new blood vessels to grow so they can obtain the nutrients necessary to continue rapidly dividing. Without a direct blood supply, a colony of cancerous cells cannot develop into a deadly tumor.
The p22 protein kills the cells that line the walls of growing blood vessels, thereby preventing new vessels from developing. Waisman hypothesizes that p22 is part of a sensitive growth control system. “If a tumor releases compounds to both promote and inhibit endothelial cell growth, it has much more control over blood vessel growth than if it released only growth factors alone,” he explained.
Waisman believes that p22’s small size means scientists will be able to determine its molecular structure. “With a small molecule, we can see it, see where it goes. Does it bind to a receptor? How can it specifically attack only capillary endothelial cells and no others? The real excitement is that we’re getting really close to figuring out how this works,” said Waisman.
The research was funded by the Canadian Institutes of Health Research.
David M. Waisman, Ph.D., is a professor in the departments of biochemistry & molecular biology, and oncology at the University of Calgary.
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