Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion.

We review the metalloproteinase/metalloproteinase inhibitor field, past work implicating metalloproteinases in invasion and metastasis, and our research using sense and antisense tissue inhibitor of metalloproteinase (TIMP) RNA to manipulate TIMP expression. Experiments on murine 3T3 cell lines downmodulated for TIMP expression have revealed a role for TIMP in controlling tumorigenesis as well as invasion; in tumors that develop from these cell lines there is an apparent increase in expression of genes encoding metalloproteinases. Growth patterns of cells engineered to produce different levels of TIMP and the characteristics of tumor cell lines derived from cells downmodulated for TIMP expression have been investigated. The evidence that metalloproteinases are an essential contributor to the metastatic process, and that TIMP is a prominent regulator, is quite conclusive.