OVEREXPRESSION OF PLASMINOGEN-ACTIVATOR INHIBITOR-2 IN HUMAN-MELANOMACELLS INHIBITS SPONTANEOUS METASTASIS IN SCID SCID MICE/

A metastatic human melanoma cell line that produces urokinase-type pla sminogen activator was stably transfected with cDNA encoding human pla sminogen activator inhibitor 2 (PAI-2). Transfected clones expressed P AI-2 at levels two to nine times higher than both the parental cell li ne and mock transfectants, as detected by ELISA of cell lysates and co nditioned medium. The clone with the highest PAI-2 expression exhibite d complete inhibition of soluble and cell-surface-bound plasminogen ac tivator activity. The level of PAI-2 overexpression in these clonal ce ll lines correlated positively with the inhibition of their ability to degrade extracellular matrix in vitro. Parental, mock-transfected, an d PAI-2-transfected cell lines produced rapidly growing tumors when in jected s.c, into the skin of mice with severe combined immunodeficienc y. The tumors producing the highest levels of PAI-2 were surrounded by a dense tumor capsule. Both parental cells and mock-transfected cells invariably metastasized from s.c. tumors to lymph nodes and lungs of mice. PAI-2-transfected cell lines produced significantly less or no m etastases. Taken together, these data indicate a critical role for pla sminogen activator activity in melanoma invasion and metastasis.