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. During this conversion, blood vessels form around the tumor, providing a dedicated supply of blood to fuel the tumor''s aggressive behavior. 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. When the body sustains a wound, it coordinates an emergency response defined by rapid cell proliferation, invasion and remodeling of connective tissues and extracellular matrix (the network of proteins and molecules around cells), cell migration, and blood vessel formation (angiogenesis). These processes, which are restorative in normal wound healing, may promote cancer by supporting tumor formation, invasion, and metastasis. With no systematic method to measure the wound-like features in cancer, however, scientists have no way to evaluate the risk that a wound-healing genetic program may pose in cancer progression.
A molecular understanding of the wound-healing process and its connection to cancer would provide insight into the nature of these similarities and perhaps provide molecular indicators of tumor progression. In an effort to create a framework for evaluating this relationship, Howard Chang and his colleagues at Stanford University developed a model to predict cancer progression based on the gene
expression profile of a cellular response to serum in cell culture.
Part of the problem with evaluating the physiological status of a tumor based on its genetic profile is that current techniques indicate only the expression, not the effect, of genes. To develop a strategy for interpreting biological outcomes from a gene expression profile, Brown''s team modeled a physiological process by exposing cultured fibroblasts to serumthe soluble fraction of coagulated bloodand tracking gene expression. Serum is encountered in the body where blood leaks out of blood vessels (in essence, all the sites of injury) and is thought to be a major initiator of the wound response. Fibroblasts exist in the connective tissue of epithelial organs (which include the digestive tract, lungs, and mammary glands) and contribute to organ development, wound healing, inflammation, and a condition called fibrosis. (Fibrosis involves the same type of extracellular matrix remodeling seen in wound healing and cancer.) And fibroblasts can promote tumor formation and metastasis when mixed with epithelial cancer cells.
Though fibroblasts from different sites in the body differ in their properties and gene expression profiles, Chang et al. found that they share a common expression pattern in response to serum. From this expression profile, the researchers identified a core group of genesa genetic signatureassociated with a serum response. Because many of the genes in the
signature were known to be involved in various wound-healing processessuch as matrix remodeling, cell motility, and angiogenesisChang 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 cancersprostate and liver-cell carcinomasand occurred variably in othersbreast, 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. Therefore, Chang et al. conclude that a wound-like phenotype is a general risk factor for metastasis and the aggressive behavior in many of the most common cancers.
These results reveal a robust and useful si