title: IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells.
abstract: OBJECTIVE
  Fibroblast growth factors (FGFs) are mitogenic polypeptides that signal via FGF receptors (FGFRs). Pancreatic ductal adenocarcinomas (PDACs) overexpress multiple FGFs, implying a potential for growth modulation. In this study we investigated the importance of the IIIc splice variant of FGFR-1 (FGFR-1 IIIc) in PDAC.
  
  
  METHODS
  Expression of FGFR-1 IIIc was determined by a ribonuclease protection assay in pancreatic cancer cell lines and in tissues. In situ hybridization was used to localize FGFR-1 IIIc messenger RNA (mRNA) in pancreatic tissues. A cDNA encoding FGFR-1 IIIc was stably transfected into the well-differentiated TAKA-1 pancreatic ductal cell line that is not responsive to FGF5 and does not express FGFR-1.
  
  
  RESULTS
  FGFR-1 IIIc was expressed in 5 of 7 pancreatic cancer cell lines and in the majority of the cancer cells in 4 of 7 PDAC samples. In vitro, TAKA-1 cells stably transfected with FGFR-1 IIIc exhibited increased basal growth; enhanced basal tyrosine phosphorylation of FGFR substrate-2 (FRS2), Shc, and phospholipase Cgamma; and increased activation of mitogen-activated protein kinase (MAPK). PD98059, an inhibitor of MAPK, suppressed the basal growth of parental and transfected clones, but the effect was more marked in clones expressing FGFR-1 IIIc. In vivo, tumor formation in nude mice was dramatically enhanced with FGFR-1 IIIc transfected (20 of 20) in comparison with sham transfected (0 of 10) cells.
  
  
  CONCLUSIONS
  Our data indicate that FGFR-1 IIIc is expressed in human pancreatic cancer cells, promotes mitogenic signaling via the FRS2-MAPK pathway, and has the potential to enhance pancreatic ductal cell transformation.
authors.affiliation: Department of General Surgery, University of Ulm, Ulm, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Kornmann
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishiwata
authors.forename: Kei
authors.initials: K
authors.lastname: Matsuda
authors.forename: Martha E
authors.initials: ME
authors.lastname: Lopez
authors.forename: Kimi
authors.initials: K
authors.lastname: Fukahi
authors.forename: Goro
authors.initials: G
authors.lastname: Asano
authors.forename: Hans G
authors.initials: HG
authors.lastname: Beger
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D015197:Carcinogenicity Tests; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010183:Pancreatic Ducts / Q000166:cytology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / 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; D014183:Transplantation, Heterologous
chemical_list: D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1