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Departments of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697
Human pancreatic ductal adenocarcinomas overexpress transforming growth factor-ßs (TGF-ßs). This overexpression has been correlated with decreased patient survival. TGF-ßs bind to a type II TGF-ß receptor (TßRII) dimer, which heterotetramerizes with a type I TGF-ß receptor (TßRI) dimer, thereby activating downstream signaling.
Purpose and Experimental Design: To determine whether blocking TGF-ß actions would suppress pancreatic cancer cell growth in vivo, we expressed a soluble TßRII, encoding amino acids 1–159 of the extracellular domain in COLO-357 human pancreatic cancer cells. This cell line expresses all of the three mammalian TGF-ß isoforms and is growth inhibited by TGF-ß in vitro.
Results: COLO-357 clones expressing soluble TßRII were no longer growth inhibited by exogenous TGF-ß1 and exhibited a marked decrease in their invasive capacity in vitro. When injected s.c. into athymic mice, these clones exhibited attenuated growth rates and angiogenesis and decreased levels of plasminogen activator inhibitor-1 mRNA as compared with tumors formed by sham-transfected cells.
Conclusions: These results indicate that endogenous TGF-ßs can confer a growth advantage in vivo to a pancreatic cancer cell line that is growth inhibited in vitro and suggest that a soluble receptor approach can be used to block these tumorigenic effects of TGF-ßs.
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