"Our findings reveal new factors influencing the process by which cells become malignant," says Zena Werb, PhD, UCSF professor of anatomy and a principal participant in both studies. "They show that factors originating outside the oncogenic cells are specifying whether there is progression in pre-malignant lesions, the nature of the malignancies that develop, in terms of aggressiveness, and such characteristics as what factor is promoting angiogenesis. And this is occurring in tumors containing very powerful oncogenes."

As the primary source of the MMP-9 protein appears to be inflammatory cells in both models, the discoveries could explain why other studies have suggested that anti-inflammatory drugs, such as COX-2 inhibitors (in mice) and nonsteroidal anti-inflammatory drugs and aspirin (in humans), appear to reduce the onset and progression of colon cancer. Several epidemiological studies have detected a 40 to 50 percent decrease in the risk of colorectal cancer in individuals who regularly use aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). COX-2 inhibitors are generally prescribed to treat the pain associated with inflammatory diseases such as arthritis.

Inflammatory cells, part of the normal immune response, migrate into developing tumor lesions, apparently in response to tissue abnormalities (or "damage'') caused by oncogene expression in the tumor cells. But ironically, says Coussens, the two studies show that the inflammatory response that occurs during carcinogenesis can help boost the angiogenic response and proliferation of oncogenic cells, by releasing MMP-9.

"This is one of the first studies that very clearly demonstrates that inflammatory cells are a critical part of the
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Contact: Jennifer O'Brien
jobrien@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
14-Mar-2001