Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that frequently metastasizes and that overexpresses transforming growth factor-beta s (TGF-beta s). To determine whether TGF-beta s can act to enhance the metastatic potential of PDAC, PANC-1 human pancreatic cancer cells were transfected with an expression construct encoding a soluble type II TGF-beta receptor (sT beta RII) that blocks cellular responsiveness to TGF-beta 1. When injected s.c. in athymic mice, PANC-1 clones expressing sT beta RII exhibited decreased tumor growth in comparison with sham-transfected cells and attenuated expression of plasminogen activator inhibitor 1 (PAI-1), a gene associated with tumor growth. When tested in an orthotopic mouse model, these clones formed small intrapancreatic tumors that exhibited a suppressed metastatic capacity and decreased expression of plasminogen activator inhibitor 1 and the metastasis-associated urokinase plasminogen activator. These results indicate that TGF-beta s act in vivo to enhance the expression of genes that promote the growth and metastasis of pancreatic cancer cells and suggest that sT beta RII may ultimately have a therapeutic benefit in PDAC.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Northern
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / prevention & control*
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Carcinoma, Pancreatic Ductal / secondary
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Female
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Gene Expression
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Genetic Vectors / genetics
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Humans
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / prevention & control*
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Plasminogen Activator Inhibitor 1 / metabolism*
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / physiology*
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Serine Proteinase Inhibitors / metabolism*
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Signal Transduction
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Transfection
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta1
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Urokinase-Type Plasminogen Activator / antagonists & inhibitors
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Urokinase-Type Plasminogen Activator / metabolism
Substances
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Plasminogen Activator Inhibitor 1
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Receptors, Transforming Growth Factor beta
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Serine Proteinase Inhibitors
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Urokinase-Type Plasminogen Activator