Soluble type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation.
Human pancreatic ductal adenocarcinomas overexpress transforming growth factor-betas (TGF-betas). This overexpression has been correlated with decreased patient survival. TGF-betas bind to a type II TGF-beta receptor (TbetaRII) dimer, which heterotetramerizes with a type I TGF-beta receptor (TbetaRI) dimer, thereby activating downstream signaling.


OBJECTIVE
To determine whether blocking TGF-beta actions would suppress pancreatic cancer cell growth in vivo, we expressed a soluble TbetaRII, 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-beta isoforms and is growth inhibited by TGF-beta in vitro.


RESULTS
COLO-357 clones expressing soluble TbetaRII were no longer growth inhibited by exogenous TGF-beta1 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-betas 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-betas.
Rowland-Goldsmith
M A
MA
Department of Medicine, University of California, Irvine, 92697, USA.
Maruyama
H
H
Kusama
T
T
Ralli
S
S
Korc
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1