Plasminogen Activation in Melanocytic Neoplasia1

A large body of experimental evidence suggests that plasminogen acti vators provide tumoral cells with efficient means to degrade extracellular matrix constituents and thereby facilitate their dissemination to distant sites. Melanocytic neoplasia encompass a spectrum of lesions exhibiting diverse clinical behavior that remain difficult to predict with current histopathological evaluations. Little information concerning the contribu tion of plasminogen activation in diagnostic specimens of human melanocytic tumors is presently available. We thus analyzed biopsy specimens of pigmented skin lesions by histolÃ3gica! techniques that identify the cellular sites of synthesis of plasminogen activators and of their inhibitors and that localize the sites of plasminogen activators-catalyzed enzymatic activities. We found that urokinase-type plasminogen activators (uPA) and plasmin ogen activator inhibitor type 1 mRNAs accumulate in atypical nevocytes and in melanoma cells, but not in benign nevocytes. However, uPAcatalyzed proteolytic activity was detected exclusively in melanomas. These observations suggest that up-regulation of the uPA gene is an early feature of melanocyte transformation and that unbalanced enzyme/ inhibitor activity is associated with the malignant phenotype. By support ing a role for uPA in melanoma invasiveness, they provide a novel tool for the evaluation of atypia in nevi.