Matrix metalloproteinases in gastrointestinal cancer

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Abstract
Sixteen MMPs have been identified to date1 (MMPs 1–19, numbers 4–6 were not used). The enzymes are structurally related and take their name from a zinc atom in the active site. The enzymes range from the well characterised interstitial collagenase (MMP-1) which degrades fibrillar collagens, to the more obscure membrane-type (MT-) MMPs whose functions and substrates are still largely to be defined. As might be expected for enzymes with such destructive potential the activity of MMPs is tightly regulated at several levels. Some MMPs do seem to be expressed constitutively in normal tissues (for example, progelatinase A in vascular smooth muscle) but in general their expression is linked to active processes of tissue remodelling such as trophoblast implantation or mammary gland involution. The enzymes are secreted in an inactive proform with an amino-terminal domain blocking the active site.2 In most cases removal of the pro-domain and consequent activation occurs extracellularly. The mechanisms of activation are not completely understood although MT1-MMP (MMP-14) does seem to be specifically responsible for the activation of progelatinase A (MMP-2).3 Once activated MMPs are subject to further control by a group of inhibitors known as “tissue inhibitors of metalloproteinases” (TIMPs), of which four have been identified to date.4