Matrilysin in early stage intestinal tumorigenesis

The demonstration that matrix metalloproteinases [MMPs] play an active role in the invasion and metastasis stages of tumor progression has led to the development of a new class of anti-metastatic chemotherapeutic agent, the m atrix metalloproteinase inhibitors [MMPIs]. We present evidence to suggest that the MMP matrilysin, in particular, plays an essential role in much ear lier stages of intestinal tumorigenesis. Matrilysin is detected in a high p ercentage of pre-invasive lesions, in contrast to its absence in most norma l tissues, and is expressed by the epithelial-derived tumor cells. Manipula ting levels of this enzyme in vitro results in cell lines with enhanced tum origenic potential, while ablating the gene in vivo leads to a significant reduction in tumor number in two different animal models of intestinal tumo rigenesis. Additionally, regulation of matrilysin gene expression appears t o be under the control of genetic pathways which are activated very early i n the tumor development sequence. Although the precise mechanism by which m atrilysin activity contributes to tumor formation is not yet clear, we prop ose that MMPIs may be of benefit as chemopreventative agents in addition to their therapeutic potential for metastatic disease.