Thrombospondin-1 and transforming growth factor beta-1 upregulate plasminogen activator inhibitor type 1 in pancreatic cancer

Controlled degradation of the extracellular matrix by proteases is crucial in tumor cell invasion. Mie have shown that thrombospondin-l (TSP-1), throu gh activation of transforming growth factor beta-1 (TGF-beta 1), regulates the plasminogen/plasmin protease system in breast cancer. To determine whet her this occurred in other epithelial neoplasms, we studied the role of TSP -1 and TGF-P I in the regulation of the plasminogen/plasmin system in pancr eatic cancer. ASPC-1 and COLO-357 pancreatic cancer cells were treated with TSP-1 or TGF-beta 1 at varying concentrations. The TSP-1 and TGF-beta 1-tr eated cells were also neared with either anti-TSP-l, anti-TSP-l receptor, o r anti-TGF-beta 1 antibodies. Urokinase plasminogen activator (uPA) and pla sminogen activator inhibitor-1 (PAI-1) expression was determined by enzyme- linked immunosorbent assay TSP-1 and TGF-beta 1 promoted a dose-dependent u pregulation of ASPC-1 and COLO-357 PAI-1 expression. The TSP-1 effect could be blocked with anti-TSP-1 or anti-TGF-beta 1 antibodies. The TGF-beta 1 e ffect could be blocked only with anti-TGF-beta 1 antibody. Anti-TSP-1 recep tor antibody blocked the TSP-1 effect on PAI-1 expression but had no effect on TGF-beta 1-mediated PAI-1 expression. Neither TSP-1 nor TGF-beta 1 had an effect on uPA production. We conclude that TSP-1, in a receptor-mediated process that involves the activation of TGF-beta 1, upregulates PAI-1 expr ession in pancreatic cancer without an effect on uPA production.