Suppression of fibroblast growth factor receptor signaling inhibits pancreatic cancer growth in vitro and in vivo.
OBJECTIVE
Fibroblast growth factors (FGFs) are mitogenic polypeptides that activate specific cell surface FGF receptors (FGFRs). Pancreatic cancers overexpress basic FGF (bFGF) and the type I FGF receptor (FGFR-1), and overexpression of bFGF has been correlated with decreased patient survival. The aim of this study was to examine the effects of abrogation of FGFR-1-dependent signaling on pancreatic cancer cell growth.


METHODS
PANC-1 human pancreatic cancer cells were transfected with a truncated FGFR-1 complementary DNA (FGFR405), resulting in the expression of a kinase-deficient receptor. Activation of endogenous FGFR-1 was assessed in immunoblot studies with antiphosphotyrosine and anti-active mitogen-activated protein (MAP) kinase antibodies. Effects on cell growth were determined in vitro and in nude mice.


RESULTS
PANC-1 clones expressing the truncated receptor showed attenuated receptor tyrosine phosphorylation and MAP kinase activation in response to bFGF, decreased basal cell growth, and a marked decrease in tumor-forming potential in vivo. Confirmatory experiments with MIA PaCa-2 pancreatic cancer cells indicated that FGFR405 also attenuated FGF-dependent MAP kinase activation in this cell line.


CONCLUSIONS
The findings suggest that FGFR-dependent signaling is crucial for pancreatic cancer growth and raise the possibility that inhibition of FGFR signaling may ultimately prove useful as a therapeutic option in patients with pancreatic cancer.
Wagner
M
M
Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine, California 92697, USA.
Lopez
M E
ME
Cahn
M
M
Korc
M
M
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000628:therapy; D010766:Phosphorylation; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D017468:Receptors, Fibroblast Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases