SUPPRESSION OF FIBROBLAST GROWTH-FACTOR RECEPTOR SIGNALING INHIBITS PANCREATIC-CANCER GROWTH IN-VITRO AND IN-VIVO

Background & Aims: Fibroblast growth factors (FGFs) are mitogenic poly peptides that activate specific cell surface FGF receptors (FGFRs). Pa ncreatic cancers overexpress basic FGF (bFGF) and the type I FGF recep tor (FGFR-1), and overexpression of bFGF has been correlated with decr eased patient survival. The aim of this study was to examine the effec ts of abrogation of FGFR-1-dependent signaling on pancreatic cancer ce ll growth. Methods: PANC-1 human pancreatic cancer cells were transfec ted with a truncated FGFR-1 complementary DNA (FGFR405), resulting in the expression of a kinase-deficient receptor. Activation of endogenou s FGFR-1 was assessed in immunoblot studies with antiphosphotyrosine a nd anti-active mitogen-activated protein (MAP) kinase antibodies. Effe cts on cell growth were determined in vitro and in nude mice. Results: PANC-1 clones expressing the truncated receptor showed attenuated rec eptor tyrosine phosphorylation and MAP kinase activation in response t o bFGF, decreased basal cell growth, and a marked decrease in tumor-fo rming potential in vivo. Confirmatory experiments with MIA PaCa-2 panc reatic cancer cells indicated that FGFR405 also attenuated FGF-depende nt 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 ma y ultimately prove useful as a therapeutic option in patients with pan creatic cancer.