IIIc Isoform of Fibroblast Growth Factor Receptor 1 Is Overexpressed in Human Pancreatic Cancer and Enhances Tumorigenicity of Hamster Ductal Cells

Gastroenterology. 2002 Jul;123(1):301-13. doi: 10.1053/gast.2002.34174.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Sequence / genetics
  • Animals
  • Base Sequence / genetics
  • Carcinogenicity Tests
  • Cell Division
  • Cell Line
  • Cell Transformation, Neoplastic*
  • Cricetinae
  • Female
  • Humans
  • In Situ Hybridization
  • Male
  • Mesocricetus
  • Mice
  • Mice, Nude
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / physiology*
  • Pancreatic Neoplasms / metabolism*
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / physiology*
  • Signal Transduction
  • Transplantation, Heterologous

Substances

  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • FGFR1 protein, human
  • Fgfr1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1