Matrix metalloproteinases as emerging targets for cancer therapy

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a key role in connective tissue-remodeling proceses. The expression and activity of these proteolytic enzymes is highly regulated by growth factors, cytokines, and hormones, as well as by interactions with specific tissue inhibitors of metalloproteinases (TIMPs). These enzymes are frequently overexpressed in many tumors, and in some cases it has been demonstrated a correlation of high MMP levels with local recurrence and increased invasive and metastatic potential of different malignant tumors. Functional studies have provided evidence that MMPs play an important role in the proteolytic destruction of extracellular matrix and basement membranes, thereby facilitating tumor invasion and metastasis. However, recent studies have indicated that MMPs may be also important in other steps of tumor evolution including neoplastic cell proliferation and angiogenesis stimulation at primary and metastatic sites. Based on the functional relevance of MMPs in tumor progression and metastasis, a number of inhibitors have been developed to try to block the activity of these enzymes. Clinical studies currently in progress will contribute to clarify whether these protease inhibitors may be part of future therapeutic strategies to control the metastatic capacity of neoplastic cells.