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

A metastatic human melanoma cell line that produces urokinase-type plasminogen activator was stably transfected with cDNA encoding human plasminogen activator inhibitor 2 (PAI-2). Transfected clones expressed PAI-2 at levels two to nine times higher than both the parental cell line and mock transfectants, as detected by ELISA of cell lysates and conditioned medium. The clone with the highest PAI-2 expression exhibited complete inhibition of soluble and cell-surface-bound plasminogen activator activity. The level of PAI-2 overexpression in these clonal cell lines correlated positively with the inhibition of their ability to degrade extracellular matrix in vitro. Parental, mock-transfected, and PAI-2-transfected cell lines produced rapidly growing tumors when injected s.c, into the skin of mice with severe combined immunodeficiency. 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 metastases. Taken together, these data indicate a critical role for plasminogen activator activity in melanoma invasion and metastasis.