Plasminogen activator regulation by transforming growth factor-beta in normal and neoplastic human urothelium

Plasminogen activators (PA) are thought to participate in the invasive and metastatic processes of malignancies and are known to be modulated by certain growth factors (Danø, K; Andreasen, P.A.; Grondahl-Hansen, J.; Kristensen, P.; Nielsen, L.S.; Skriver, L. Adv. Cancer Res. 44:139-266; 1985 and Laiho, M.; Keski-Oja, J. Cancer Res. 49:2533-2553; 1989). This report describes the effect of TGF-beta on the regulation of secreted PA activity produced by human fetal urothelium and neoplastic urothelial cell lines. Epidermal growth factor was previously shown to induce substantially different effects on PA production by normal versus neoplastic urothelial (Dubeau, L.; Jones, P.A.; Rideout, W.M.; Laug, W.E. Cancer Res. 48:5552-5556; 1988). This report demonstrates that log phase normal urothelium, but not transformed cells, responded to TGF-beta (1-10 ng/mL) by diminishing the total secreted PA activity. Northern and western analyses showed that the reduction in protease activity resulted from an increased level of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein. Additionally, northern analysis of total mRNA levels at varying cell densities demonstrated modulation of tPA, PAI-1, and TGF-beta transcripts in normal urothelial cells as a function of growth in vitro, suggesting the presence of an intact regulatory pathway to control extracellular proteolysis.