IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells.

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.

• Authors: Marko Kornmann, Toshiyuki Ishiwata, Kei Matsuda, Martha E Lopez, Kimi Fukahi, Goro Asano, Hans G Beger, Murray Korc
• Journal: Gastroenterology (Gastroenterology) Vol. 123 Issue 1 Pg. 301-13 (Jul 2002) ISSN: 0016-5085 [Print] United States
• PMID: 12105858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• 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, physiology)
• Pancreatic Neoplasms (metabolism)
• RNA, Messenger (metabolism)
• Receptor Protein-Tyrosine Kinases (genetics, physiology)
• Receptor, Fibroblast Growth Factor, Type 1
• Receptors, Fibroblast Growth Factor (genetics, physiology)
• Signal Transduction
• Transplantation, Heterologous