Directed migration of murine and human tumor cells to collagenases and other proteases.

Tumor cell motility and the passage of tumor cells through various tissue matrices, including basement membrane, are important components of the metastatic process. Proteolytic enzymes, including a type IV collagen-specific collagenase, have been demonstrated to play a significant role in extracellular matrix and basement membrane degradation. In addition, exogenous collagenase has been shown to enhance the motility of some tumor cells independent of its effect on collagen-containing material. Previous studies have also indicated that collagen fragments are chemotactic for many tumor cells. We therefore studied the effect of type I and type IV collagen-specific collagenases, other enzymes involved in collagenase activation and connective tissue degradation, and subsequent collagen degradation products on the directed migration of tumor cells. We report that type I and type IV collagen-specific mammalian collagenases were potent chemoattractants as were native type I and type IV collagens and collagen fragments. Collagenase inhibitor SC44483 inhibited the type IV collagenase-stimulated migration. Collagenase pretreatment of the tumor cells potentiated the migratory response of the tumor cells to collagen and collagen fragments. The plasminogen activator, urokinase, as well as plasminogen itself also enhanced the directed migration of tumor cells in concentrations that suggest involvement of the appropriate cell surface receptor. The chemotactic response of tumor cells to the proteases studied extends the prior report of a role for collagenases and other matrix-active enzymes in tumor cell behavior in addition to matrix degradation.