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Wound Repair and Deadliest Cancers Share Genetic Signature

By Nancy Touchette

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Cancer
Microarrays

Wounds share many features with cancerous tumors. Both need new blood vessels and often involve the invasion and growth of new cells. Now new studies suggest that for reasons yet unknown, the genes active during wound healing are also activated in cancers with the worst outcomes. The new studies may lead to new ways to diagnose and treat the most deadly types of tumors.

A gene active in wound healing is also more active in breast cancer tissue (right) compared to normal breast tissue (left).

Researchers at Stanford University in Stanford, California, used DNA microarrays, or gene chips, to study gene activity in cultured cells known as fibroblasts. Scientists often study fibroblasts to learn about wound repair because the cells, which are found in the connective tissue surrounding most organs, are activated when tissue is damaged.

“The initiating event in a wound is a broken blood vessel,” says Howard Chang, a postdoctoral researcher who conducted the studies in Patrick Brown’s laboratory at Stanford. “Blood spills out of the tissues and this signals the fibroblasts to respond.”

To simulate this process, Chang and his colleagues exposed the cultured cells to serum—the part of the blood that is left once the cells and platelets coagulate. The researchers found a distinct pattern of gene activity in the cells, involving more than 500 genes. This pattern, or gene signature, was unique to the stimulated cells.

More than 15 years ago, Harold F. Dvorak of Beth Israel Deaconess Medical Center in Boston, Massachusetts, described cancer growth and metastasis as “wound healing gone awry.” This analogy prompted the Stanford researchers to explore the wound-cancer connection. They searched tissue repositories for biopsy samples and examined cells cultured from 10 different types of tumors.

The quest revealed the wound-healing signature in samples from breast, lung, gastric, prostate, and liver cancers. And those tumors with the signature were more dangerous and more likely to metastasize, or spread. For example, breast tumors with the signature were 3.3 times more likely to metastasize within five years than those without it.

“We found that cancers neatly segregated into two different types: those that had the wound signature and those that didn’t,” says Chang. “Patients with the wound-like signature had worse outcomes and greater chance of metastasis and death.”

Chang said breast cancer patients who were tested both before and after anticancer treatment showed the same pattern, even after tumors were excised and radiated or treated with chemotherapy drugs. This suggests that tumor cells with the signature are stable and persistent, and not easily killed by standard treatments.

The findings may help better determine which patients may benefit from a particular therapy. For example, patients with the wound-healing signature might benefit from a more aggressive treatment.

The research could also be useful for scientists testing a new class of drugs called angiogenesis inhibitors to stop the spread of cancer. The drugs, which block the growth of new blood vessels in tumor cells, have had mixed reviews in clinical trials. But the drugs might be effective in patients with the wound-healing signature, if doctors could identify them, says Chang.

Chang, H.Y. et al. Gene expression signature of fibroblast serum response predicts human cancer progressions similarities between tumors and wounds. PloS Biology 2, 1-9 (February, 2004).

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