Extracellular matrix 6: Role of matrix metalloproteinases in tumor invasion and metastasis

Tumor invasion and metastasis formation are major obstacles for successful cancer therapy. Metastasis is a complex multistep process that requires sequential interactions between the invasive cell and the extracellular matrix. A model system for tumor invasion of extracellular matrix barriers has been developed, and application of this model has facilitated our understanding of the molecular mechanisms of metastasis formation. This model consists of three steps: tumor cell adhesion, extracellular matrix proteolysis, and cell migration. The role of the matrix metalloprotease enzymes in tumor cell-mediated extracellular matrix proteolysis is well established. We review the functional domain structure of the matrix metalloprotease enzymes in general and specifically the interaction of metastasis-associated gelatinase A (72-kDa type IV collagenase) with the tissue inhibitor of metalloproteases-2 (TIMP-2). We also discuss the physiologic activation of the matrix metalloprotease enzymes and the specific cellular mechanism of action of gelatinase A.