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. We have shown that thrombospondin-1 (TSP-1), through activation of transforming growth factor beta-1 (TGF-beta1), regulates the plasminogen/plasmin protease system in breast cancer. To determine whether this occurred in other epithelial neoplasms, we studied the role of TSP-1 and TGF-beta1 in the regulation of the plasminogen/plasmin system in pancreatic cancer. ASPC-1 and COLO-357 pancreatic cancer cells were treated with TSP-1 or TGF-beta1 at varying concentrations. The TSP-1 and TGF-beta1-treated cells were also treated with either anti-TSP-1, anti-TSP-1 receptor, or anti-TGF-beta1 antibodies. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression was determined by enzyme-linked immunosorbent assay. TSP-1 and TGF-beta1 promoted a dose-dependent upregulation of ASPC-1 and COLO-357 PAI-1 expression. The TSP-1 effect could be blocked with anti-TSP-1 or anti-TGF-beta1 antibodies. The TGF-beta1 effect could be blocked only with anti-TGF-beta1 antibody. Anti-TSP-1 receptor antibody blocked the TSP-1 effect on PAI-1 expression but had no effect on TGF-beta1-mediated PAI-1 expression. Neither TSP-1 nor TGF-beta1 had an effect on uPA production. We conclude that TSP-1, in a receptor-mediated process that involves the activation of TGF-beta1, upregulates PAI-1 expression in pancreatic cancer without an effect on uPA production.