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Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that frequently metastasizes and that overexpresses transforming growth factor-ßs (TGF-ßs). To determine whether TGF-ßs 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-ß receptor (sTßRII) that blocks cellular responsiveness to TGF-ß1. When injected s.c. in athymic mice, PANC-1 clones expressing sTßRII 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-ßs act in vivo to enhance the expression of genes that promote the growth and metastasis of pancreatic cancer cells and suggest that sTßRII may ultimately have a therapeutic benefit in PDAC.

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