Biology and Regulation of the Matrix Metalloproteinases

Abstract

Matrix metalloproteinases (MMPs) are the predominant family of enzymes that degrade extracellular matrix and cell surface molecules. Like the proteins they modify, the MMPs and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play a critical role in diverse physiologic and pathologic processes, including embryonic development, tissue morphogenesis, wound repair, arthritis, and cancer (1–3). Indeed, several MMPs were first cloned from cancer cell lines, and most human MMPs have been detected in one tumor cell line or another (1,4) In actual carcinomas however, the MMPs are usually expressed by the adjacent and intervening stromal cells rather than by the malignant cells themselves (1,4) Nevertheless, the overexpression of MMPs usually correlates with more aggressive tumor behavior and a poor prognosis. Moreover, cancer cells can be made even more aggressive in vitro and in vivo by MMP overexpression or TIMP down-regulation, or they can be made less aggressive by MMP down-regulation, TIMP overexpression, or the addition of exogenous MMP inhibitors. Thus several MMPs have been shown to act as key agonists during tumor invasion, metastasis, and angiogenesis (1,4) In addition, some MMPs may contribute to initial tumor development (5–9), thus raising the possible clinical utility of inhibiting select MMPs during early as well as late stages of cancer progression.