POLYOMA MIDDLE T-INDUCED VASCULAR TUMOR-FORMATION - THE ROLE OF THE PLASMINOGEN-ACTIVATOR PLASMIN SYSTEM

The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells, leading to the formation of vascular tumors in newb orn mice, Transformed endothelial (End.) cell lines established from s uch tumors exhibit altered proteolytic activity as a result of increas ed expression of urokinase-type plasminogen activator (uPA) and are ca pable of inducing vascular tumors efficiently when injected into adult mice, In this study we have used mice lacking components of the PA/pl asmin system to analyze the role of this system in the transformation process and in tumor growth, We found that the proteolytic status of t he host is not a critical determinant for PymT-induced vascular tumor formation. In addition, the lack of either uPA or tissue-type PA (tPA) activity is not limiting for the establishment and proliferation of E nd, cells in vitro, although the combined loss of both PA activities l eads to a marked reduction in proliferation rates, Furthermore, the in vitro morphogenetic properties of mutant End, cells in fibrin gels co uld only be correlated with an altered proteolytic status in cells lac king both uPA and tPA. However, in contrast with tumors induced by Pym T itself, the tumorigenic potential of mutant and wild-type End, cell lines was found to be highly dependent on the proteolytic status of bo th the tumor cells and the host. Thus, genetic alterations in the PA/p lasmin system affect vascular tumor development, indicating that this system is a causal component in PymT-mediated oncogenesis.