Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines.
Pancreatic ductal adenocarcinomas (PDACs) overexpress several members of the fibroblast growth factor (FGF) family of ligands and the type I FGF receptor (FGFR-1), and enhanced FGF-2 protein levels correlate with shorter postoperative survival of patients with PDAC. In this study, we investigated the effects of FGF-2 on cell proliferation and mitogen-activated protein kinase (MAPK) activation before and after abrogation of FGFR-1-dependent signaling in 4 pancreatic cancer cell lines (ASPC-1, COLO-357, MIA-PaCa-2, and PANC-1). Signaling was blocked by infecting the cells with an adenoviral vector encoding for a truncated FGFR-1 (AdtrFGFR-1). FGF-2 enhanced the growth of all 4 cell lines and activated MAPK in 3 of these cell lines. Infection with the AdtrFGFR-1 virus resulted in abundant expression of the truncated FGFR-1 at the RNA and protein level, markedly attenuated FGF-2-induced proliferation in all 4 tested cell lines, and decreased FGF-2-dependent MAPK activation in the 3 cell lines in which FGF-2 activated this pathway. These findings suggest that FGFR-1-mediated mitogenesis in multiple pancreatic cancer cells can be efficiently blocked with an adenoviral vector encoding a truncated FGFR-1, raising the possibility that AdtrFGFR-1 may ultimately have a therapeutic role in PDAC.
Kleeff
Jörg
J
Division of Endocrinology, Department of Medicine, University of Heidelberg, Germany.
Kothari
Nayantara H
NH
Friess
Helmut
H
Fan
Hung
H
Korc
Murray
M
D000256:Adenoviridae / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases