Jan. 14, 2004 The idea that cancer cells go through a fateful transition that turns them into fast-growing, invasive, metastasizing tumors first surfaced in the early 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 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 tumor and wounds, Howard Chang and his colleagues in Patrick Brown's lab at Stanford University examined the gene expression profile of fibroblasts responding to serum in 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.
Though fibroblasts from different sites in the body differ in their properties and gene expression profiles, Brown and colleagues found that they share a common expression pattern in response to serum. From this expression profile, Chang et al. 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--Chang et al. 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. And the serum-response expression signature provides a valuable new diagnostic tool for predicting tumor behavior and determining a patient's prognosis.
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