Predicting Progression of Common Cancers

Wound-healing genes influence tumor growth

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Howard Chang, MD, PhD, and colleagues say wound-like genetic signatures are always present in certain cancers, a finding that may change the way cancer is treated. (Stanford University)

Fibroblasts are involved in wound healing, and serum is encountered in the body where blood leaks out of blood vessels (such as sites of injury) and is thought to be a major initiator of the wound-healing response. (Public Library of Science)

The idea that cancer cells go through a fateful transition that turns them into fast-growing, invasive, metastasizing tumors first surfaced in the 1970s. By the mid-1980s, histological analysis revealed a similarity between the tumor "microenvironment" and that of a healing wound, prompting Harvard pathologist Harold Dvorak, MD, to describe cancer as a wound that does not heal. With no systematic method to measure the "wound-like" features in cancer, however, scientists had no way to evaluate the risk that a wound-healing genetic program may pose in cancer progression.

In an effort to create a framework for evaluating the relationship between tumors and wounds, Howard Chang, MD, PhD, a postdoctoral scholar, Patrick Brown, MD, PhD, professor of biochemistry, and colleagues at Stanford University, Stanford, Calif., examined the gene expression profile of fibroblasts responding to a serum in a cell culture – a process that shares certain features with wound healing. Fibroblasts are involved in wound healing, and serum is encountered in the body where blood leaks out of blood vessels (such as sites of injury) and is thought to be a major initiator of the wound-healing response. The work appears in a recent issue of Public Library of Science Biology.

Though fibroids from different sites in the body differ in their properties and gene expression profiles, the researchers found they share a common expression pattern in response to serum. From this expression profile, the researchers identified a core group of genes – a genetic signature – associated with a serum response. Because many of the genes in the signature were known to be involved in various wound-healing processes, such as matrix remodeling, cell motility and angiogenesis, they used this signature as a surrogate marker to measure how much tumors may be like wounds.

When they compared the wound-like genetic signature with the expression profiles of various clinical tumor samples, they found the signature was always present in certain cancers (prostate and liver cell carcinomas) and occurred variably in others (breast, lung and gastric carcinomas). In each of these three latter types of tumors, patients with tumors carrying the serum-activated wound-like genetic signature had a significantly increased risk of metastasis and death compared to patients with tumors that lacked the signature.

These results reveal a similarity between the molecular programs in normal wound healing and tumor progression and metastasis and suggest that a wound-like phenotype is a general risk factor for metastasis and aggressive behavior in many of the most common cancers. The serum-response express-ion signature provides a valuable new diagnostic tool for predicting tumor behavior and determining a patient's prognosis.

"This is a feature we can find early on in the disease and it could change the way cancer is treated," says Chang.

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— Public Library of Science