Invasion of cells across extracellular matrix barriers requires attachment of cells to the matrix, creation of a proteolytic defect in the matrix, and migration of the cells through the defect. To date, alterations in the balance between matrix metalloproteinases (MMPs) and their inhibitors have been shown to alter cellular invasion only through effects on matrix degradation. We used a retroviral infection system to over- and underproduce tissue inhibitor of metalloproteinase-2 (TIMP-2) in human A2058 melanoma cells. Our results indicate that altering the balance of MMPs and TIMP-2 through genetic manipulation of TIMP-2 production modulates not only proteolysis of the extracellular matrix but also cell attachment to the extracellular matrix and motility of cells through matrix components. Altering the production of TIMP-2 also results in the ability of cells to form foci. These results implicate the MMPs and their inhibitors in all aspects of the cellular invasion cascade. This supports the hypothesis that highly invasive cell lines establish a balance of MMPs and inhibitors that is optimal for invasion, and alteration of this balance in either direction results in perturbation of the invasive phenotype.
