TISSUE-TYPE PLASMINOGEN ACTIVATOR-INDUCED INVASION AND METASTASIS OF MURINE MELANOMAS

The role of tissue-type plasminogen activator (tPA) in the 'spontaneou s' as well as 'experimental' metastasis of ocular melanomas in mice wa s evaluated by transfecting the D5.1G4 murine melanoma cell line that possesses low metastatic activity and low tPA activity with a full len gth cDNA encoding human tPA. For comparison, a highly metastatic melan oma cell line (Queen's) that constitutively expresses high tPA product ion, was transfected with a cDNA coding for human plasminogen activato r inhibitor type 1 (PAI-1). Unlike non-transfected controls, transfect ed D5.1G4 melanoma cells expressed high levels of tPA and produced ext ensive pulmonary metastases following intravenous injection. By contra st, PAI-1 transfected Queen's melanoma cells expressed low tPA activit y and displayed significantly reduced metastatic potential compared wi th nontransfected controls. Moreover, PAI-1 transfected Queen's melano ma cells did not metastasize from the eye while nontransfected parenta l cells produced extensive spontaneous metastases. Expression of tPA a ctivity in transfected and nontransfected cell lines was completely bl ocked by an anti-tPA antibody. This antibody significantly inhibited t he organ localization and frequency of lung metastases of both Queen's and tPA-transfected D5.1G4 melanomas. This study demonstrates that tP A is involved in the metastasis of murine intraocular melanomas.