TY - JOUR
T1 - Thrombospondin-1 and Transforming Growth Factor Beta-1 Upregulate Plasminogen Activator Inhibitor Type 1 in Pancreatic Cancer
AU - Albo, Daniel
AU - Berger, David H.
AU - Vogel, Jon
AU - Tuszynski, George P.
N1 - Funding Information:
Tumor cell metastasis is a complex, multistep process that is believed to involve the controlled degradation of the tumor cell-associated extracellular matrix and basement membrane by proteases. The plasminogen/plasmin system is one of the main protease systems involved in malignancy. 1 Activation of plasminogen to plasmin on tumor cells is performed by the urokinase-type plasminogen activator (uPA). 2 By binding to a specific receptor on the cell surface, the proteolytic activity of uPA becomes more efficient and localized to the tmnor cell surface. Localization of enzymes to the tumor cell surface increases pericellular proteolysis and enhances the invasive potential of the tumor cells. 3-6 Although degradation of the extracellular matrix is necessary for tumor cell invasion, excessive matrix degradation has been shown to inhibit tumor cell migration and prevent invasion. 7-1° Plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of uPA, has been shown to localize to the extracellular matrix in several malignancies in association with matrix proteins such as vitronectin. TM PAI-1 has been shown to promote breast tumor cell invasion by preventing excessive matrix degradation by tumor-associated plasmin-mediated proteolytic activity. 9 Considerable evidence indicates that increased levels of tumor-associated PAI-1 are a strong, independent prognostic indicator of poor clinical outcome in cancer patients. 13,14 A growing body of evidence points to the extracellular matrix as a key component in modulating plasminogen activation by providing molecules that reg- From the Departments of Surgery,P athology, and LaboratoryM edicine,A lleghenyU niversityo f the Health Sciences,P hiladelphia, Pa. Supported in part by National Institutes of Health grants CA65675 and CA69722 (Dr. Tuszysnki). Dr. Berger is the recipient of an AmericanC ancer SocietyC linical Career DevelopmentA ward 96-09. Presented at the Thirty-Eighth AnnualM eeting of The Societyf or Surgeryo f the AlimentaryT ract, Washington, D.C., May 1I - 14, 1997. Reprint requests: David H. Berger, M.D., Department of Surgery, AlleghenyU niversity of the Health Sciences, 3300 Henry Ave., Philadelphia, PA 19129.
PY - 1999
Y1 - 1999
N2 - 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-β1), 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-β1 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-β1 at varying concentrations. The TSP-1 and TGF-β1-treated cells were also treated with either anti-TSP-1, anti-TSP-1 receptor, or anti-TGF-β1 antibodies. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression was determined by enzyme-linked immunosorbent assay. TSP-1 and TGF-β1 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-β1 antibodies. The TGF-β1 effect could be blocked only with anti-TGF-β1 antibody. Anti-TSP-1 receptor antibody blocked the TSP-1 effect on PAI-1 expression but had no effect on TGF-β1-mediated PAI-1 expression. Neither TSP-1 nor TGF-β1 had an effect on uPA production. We conclude that TSP-1, in a receptor-mediated process that involves the activation of TGF-β1, upregulates PAI-1 expression in pancreatic cancer without an effect on uPA production.
AB - 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-β1), 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-β1 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-β1 at varying concentrations. The TSP-1 and TGF-β1-treated cells were also treated with either anti-TSP-1, anti-TSP-1 receptor, or anti-TGF-β1 antibodies. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression was determined by enzyme-linked immunosorbent assay. TSP-1 and TGF-β1 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-β1 antibodies. The TGF-β1 effect could be blocked only with anti-TGF-β1 antibody. Anti-TSP-1 receptor antibody blocked the TSP-1 effect on PAI-1 expression but had no effect on TGF-β1-mediated PAI-1 expression. Neither TSP-1 nor TGF-β1 had an effect on uPA production. We conclude that TSP-1, in a receptor-mediated process that involves the activation of TGF-β1, upregulates PAI-1 expression in pancreatic cancer without an effect on uPA production.
KW - Pancreatic neoplasms
KW - Plasminogen activator inhibitor
KW - Thrombospondin-1
KW - Transforming growth factor beta-1
KW - Urokinase plasminogen activator
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U2 - 10.1016/S1091-255X(99)80058-4
DO - 10.1016/S1091-255X(99)80058-4
M3 - Article
C2 - 10482694
AN - SCOPUS:0033155804
VL - 3
SP - 411
EP - 417
JO - Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
JF - Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
SN - 1091-255X
IS - 4
ER -