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When the skin is cut, blood is released onto the epidermis (orange). Albumin proteins in the blood plasma harden into crystals (pink) over the wound, joining with other proteins to form a clot. One of the many molecules involved in healing, albumin helps maintain proper levels of hormones and calcium in the blood, and also assists water flow between tissues and the bloodstream.
This work is a real breakthrough, says Paul Martin, a developmental cell biologist at the University of Bristol in England. "Now we have an immediate route to get at the genetics of this process; we can trawl through 50 to 100 genes and see what's important," he says. Indeed, Krasnow and Galko are now busily knocking out other genes and repeating their experiments on the mutants.
They're also getting help from a group down the hall at Stanford that is probing the link between wound healing and cancer. HHMI investigator Patrick O. Brown, Howard Y. Chang, and their colleagues took human fibroblasts—a kind of skin cell that plays a role both in normal tissues and in some tumors—and exposed them to serum derived from clotted blood. Then, using DNA microarray technology to see which genes were turned on, they identified a stereotypical pattern, or "wound-response signature," that involves about 500 genes. This information is helping Krasnow and Galko select candidate genes for testing in their Drosophila model.
Equally important, Brown's team confirmed that wound healing and cancer growth are truly related. For decades, researchers have theorized that "wound healing gone awry" makes tumor cells migrate and proliferate. One piece of evidence is that people suffering from chronic inflammation, which involves cycles of damage and repair, also have high rates of cancer. Last year, Brown's group finally found a link. "We found a striking and consistent tendency of tumors, compared with normal tissue, to express the signature wound-healing genes," he says.
"This is not at all surprising," says Martin, "but it's fantastic to have real molecular evidence." And, notes Brown, it raises the possibility that interventions targeting wound healing might also help treat cancer.
Already, the Brown lab's efforts suggest one potential medical benefit: a test to identify early those cancer patients who will likely need follow-up treatment such as chemotherapy. The researchers found that tumors of the breast, lung, and stomach were more likely to metastasize if they had a gene-expression signature suggestive of active wounds. They published the work in the March 8, 2005, issue of the Proceedings of the National Academy of Sciences. The team is now investigating ways to develop a simple "wound-response" test that would be useful in the cancer clinic.
Image: SPL / Photo Researchers, Inc.