Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis.
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.
Rowland-Goldsmith
Melissa A
MA
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697, USA.
Maruyama
Haruhisa
H
Matsuda
Kei
K
Idezawa
Takenao
T
Ralli
Monica
M
Ralli
Sonia
S
Korc
Murray
M
D000818:Animals; D015152:Blotting, Northern; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D015842:Serine Proteinase Inhibitors; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D014568:Urokinase-Type Plasminogen Activator