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.
Albo
D
D
Department of Surgery, Pathology, and Laboratory Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19129, USA.
Berger
D H
DH
Vogel
J
J
Tuszynski
G P
GP
D000912:Antibodies, Neoplasm / Q000276:immunology; D018955:CD36 Antigens / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005341:Fibrinolysin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016014:Linear Models; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D013223:Statistics as Topic; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D000912:Antibodies, Neoplasm; D018955:CD36 Antigens; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator