Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1

In vivo tumor progression in mice with targeted deficiencies in urokinase-t ype plasminogen activator (UPA(-/-)) and its inhibitor, plasminogen activat or inhibitor-1 (PAI-1(-/-)), was studied using a fibrosarcoma tumor model. Murine T241 fibrosarcoma cells were s.c, implanted into three groups of mir e with the following genotypes, wild-type (WT), UPA(-/-), and PAI-1(-/-). A significantly diminished primary tumor growth in UPA(-/-) and PAI-1(-/-) m ice occurred, relative to WT mice. Tumors in UPA(-/-) and PAI-1(-/-) mice d isplayed lower proliferative and higher apoptotic indices and displayed a d ifferent neovascular morphology, as compared with WT mice. These results ar e consistent with the decreased growth rates of this tumor in these gene-de leted mice. Immunohistochemical analyses of the tumors revealed a decrease in vascularity and vascular endothelial growth factor expression only in tu mors in PAI-1(-/-) mice. Analyses of the relative extents of corneal angiog enesis in these same animals, induced by basic fibroblast growth factor, co rroborated the resistance of PAI-1(-/-) mice to neovascularization. The res ults obtained suggest that the host fibrinolytic system plays an important role in tumor growth in this model. Alterations in host expression of compo nents of this system may alter tumor growth and dissemination by affecting the balance between tumor cell death and proliferation, as well as extracel lular matrix changes needed for invasiveness and angiogenesis.