The expression of different components of the plasminogen activator (PA)/plasmin system was explored in a series of colorectal neoplasia. We have found that urokinase (uPA) and urokinase receptor (uPA-R) gene expression is upregulated in adenomas and carcinomas, and that uPA/uPA-R production is confined to stromal cells in the proximity of epithelial proliferations. In addition, in adenomas, the focal increase in uPA mRNA is not systematically coupled to detectable enzymatic activity, whereas in carcinomas, uPA mRNA accumulation is consistently associated with detectable but variable levels of enzymatic activity. In contrast, in the tumor vasculature, tissue-type plasminogen activator-mediated proteolysis is considerably reduced when compared to normal mucosal and submucosal vessels; this reduction in plasmin formation appears to result from the highly increased production of plasminogen activator inhibitor type 1 by endothelial cells. Our observations demonstrate that colorectal neoplasia are associated with marked alterations in the extracellular proteolytic balance controlled by the PA/plasmin system. They show that contrasting disturbances in plasmin formation take place in distinct stromal compartments but not in epithelial cells, and that these disturbances are maximal during invasive neoplasia. Altogether, our results raise the possibility that alterations in plasmin formation should not be exclusively regarded as promoters of cancer cell invasiveness.