LACK OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 EFFECT IN A TRANSGENIC MOUSE MODEL OF METASTATIC MELANOMA

Tumor cell invasion and metastasis is a complex, multistep process tha t is postulated to require degradation of extracellular matrix at seve ral steps, Urokinase-type plasminogen activator (uPA) is expressed on the cell surface of B16 murine melanoma cells and is thought to contri bute to the pericellular proteolysis necessary for tumor cell migratio n. In vitro modification of B16 melanoma cell surface uPA activity has been shown to alter the invasive and metastatic potential of these mu rine melanoma cells in vivo. Plasminogen activator inhibitor-1 (PAI-1) , a rapid inhibitor of both uPA and tissue-type plasminogen activator (tPA) is the major physiologic regulator of plasminogen activator acti vity. To test the role of host PAI-1 in the invasive and metastatic ca pacity of B16 melanoma cells we analyzed local tumor growth and pulmon ary metastasis in transgenic mice engineered to overexpress murine PAI -1 in multiple tissues including lung, and in mice completely deficien t in PAI-1. No significant difference in the number of pulmonary metas tases was observed after intravenous inoculation of tumor cells into P AI-1-overexpressing and PAI-1-deficient mice when compared with wild-t ype controls. Similarly, in a spontaneous metastasis model, PAI-1-over expressing and PAI-1-deficient mice demonstrated no difference in prim ary tumor size or overall survival. These data demonstrate that wide v ariations of host PAI-1 expression, from complete absence to marked ov erexpression, does not significantly influence the metastatic potentia l of B16 melanoma cells in a murine model. (C) 1996 by The American So ciety of Hematology.