REDUCED METASTASIS OF POLYOMA-VIRUS MIDDLE T-ANTIGEN-INDUCED MAMMARY-CANCER IN PLASMINOGEN-DEFICIENT MICE

To investigate the role of plasmin(ogen) in mammary tumor development and progression, plasminogen-deficient mice were crossed with transgen ic mice expressing Polyoma middle T antigen under the control of the m ouse mammary tumor virus long terminal repeat. Virgin females carrying the Polyoma middle T antigen uniformly developed multiple, bilateral mammary tumors, regardless of the presence or absence of circulating p lasminogen. Both the age at which these tumors became palpable and sub sequent tumor growth were indistinguishable between plasminogen-defici ent mice and plasminogen-expressing littermates. Hoowever, plasminogen was found to greatly modify the metastatic potential in this model sy stem; lung metastasis in plasminogen-deficient mice was significantly reduced as compared to littermate controls with respect to frequency o f occurrence, total number of metastases, and total metastatic tumor b urden. Plasminogen activators, as well as other key factors that gover n the conversion of plasminogen to plasmin, were expressed within the mammary tumors, suggesting that the plasminogen/plasmin system may pro mote metastasis by contributing to tumor-associated extracellular prot eolysis. The data provide direct evidence that plasmin(ogen) is a tumo r progression factor in PymT-induced mammary cancer, and support the h ypothesis that hemostatic factors play an important role in tumor biol ogy.