Wagner M, Lopez M E, Cahn M, Korc M
Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine, California 92697, USA.
Gastroenterology. 1998 Apr;114(4):798-807. doi: 10.1016/s0016-5085(98)70594-3.
BACKGROUND & AIMS: 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.
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.
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.
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.
