Tissue plasminogen activator (tPA) is absent from normal human pancreas and is expressed in 95% of human pancreatic adenocarcinomas. We have analyzed the expression of components of the tPA system in murine pancreatic tumors and the role of tPA in neoplastic progression. Transgenic mice expressing T antigen and c-myc under the control of the elastase promoter (Ela1-TAg and Ela1-myc, respectively) were used. tPA was undetectable in normal pancreas, acinar dysplasia, ductal complexes, and in all acinar tumors. By contrast, it was consistently detected in Ela1-myc tumors showing ductal differentiation. Crossing transgenic Ela1-myc with tPA-/- mice had no effect on the proportion of ductal tumors, indicating that tPA is not involved in the acinar-to-ductal transition. Ela1-myc:tPA-/- mice showed an increased survival in comparison to control mice. All ductal tumors, and none of the acinar tumors, overexpressed the tPA receptor annexin A2, suggesting its participation in the effects mediated by tPA. Our findings indicate that murine and human pancreatic ductal tumors share molecular alterations in the tPA system that may play a role in tumor progression.