More broadly, says Werb, the two studies suggest that, even in the absence of MMP-9, there are multiple mechanisms that influence the progression of a cancer. "This is incredibly important to recognize in terms of how human cancers behave," she says. "There are a progressive series of events occurring, and the question of what factors propel that progression haven't been addressed much.

"Now we're seeing for the first time that there are these layers of hierarchies or events involved. In these two studies we've highlighted just one that alters the tumor micro-environment."

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In the skin carcinoma study, (Cell, Vol. 103, 481-490, October, 2000) the researchers discovered that, in most cases, MMP-9 increased the proliferation of oncogene-expressing cells, enhanced conversion of developing cancers into frank carcinomas, and reduced the frequency with which tumor cells terminally differentiated, or matured, a key step in normal cell health.

However, underscoring the complexity of cancer development, the researchers also determined that when the same type of tumors developed in the absence of MMP-9, those tumors were less differentiated, indicative of a higher grade tumor.

This conflicting aspect of the finding could explain why some MMP inhibitors have proven ineffective against late-stage cancers in clinical trials.

"It's possible that the same enzyme does the opposite thing at different stages of a tumor's growth, because its targets are different," says Werb. "Maybe the same things that help set up the tumor are then used by surveillance cells to try to do it in.

"Usually mouse model studies indicate how many mice or which mice develop tumors, or how big a tumor will get. In our study, we've gone beyond that to ask, `What is special about the 20 or 50 percent that
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Contact: Jennifer O'Brien
jobrien@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
14-Mar-2001