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FGFR2 isoforms support epithelial-stromal interactions in thyroid cancer progression

Miao Guo1, Wei Liu, Stefano Serra

  • 1The Ontario Cancer Institute, Department of Medicine, University Health Network, Toronto, Ontario, Canada.

Cancer Research
|February 21, 2012
PubMed

Insights

Fibroblast growth factor (FGF) receptor variants FGFR2-IIIb and FGFR2-IIIc show tumor-suppressive effects in thyroid cancer cells but promote fibroblast growth, highlighting context-dependent functions.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Fibroblast growth factor (FGF) receptor (FGFR) expression is frequently dysregulated in human thyroid cancer.
  • Alternate splicing of FGFR2 generates distinct isoforms, FGFR2-IIIb and FGFR2-IIIc, with varying extracellular structures.

Purpose of the Study:

  • To investigate the functional roles of FGFR2-IIIb and FGFR2-IIIc isoforms in modulating thyroid cancer cell behavior.
  • To understand the impact of these FGFR isoforms on tumor growth, invasion, and metastasis in vivo and in vitro.
  • To explore the influence of cellular context on the growth-promoting or suppressing activities of FGFR isoforms.

Main Methods:

  • Enforced expression of FGFR2-IIIb or FGFR2-IIIc in thyroid epithelial cancer cells.
  • Assessment of gene expression changes (fibronectin, MAGE-A3, MMP9, p21) and Rb dephosphorylation.
  • In vitro invasion assays and in vivo tumor growth and metastasis studies using xenograft models.
  • Co-implantation experiments with epithelial and fibroblast cells expressing specific FGFR isoforms.

Main Results:

  • Expression of FGFR2-IIIb or FGFR2-IIIc in thyroid cancer cells reduced fibronectin, MAGE-A3, and MMP9, while increasing p21 and Rb dephosphorylation.
  • Both isoforms exhibited tumor-suppressive properties, diminishing invasion in vitro and reducing tumor growth and metastasis in vivo.
  • In contrast, these isoforms stimulated fibroblast cell growth.
  • Co-expression of FGFR2-IIIb in epithelial cells and FGFR2-IIIc in fibroblasts enhanced tumor progression, indicating context-dependent effects.

Conclusions:

  • Cellular context is crucial in determining the growth-modulating properties of FGF receptor isoforms.
  • Alternative splicing of FGFR2 generates heteroisoforms with distinct epithelial-stromal effects critical for FGF-mediated growth promotion in thyroid cancer.
  • These findings underscore the complex roles of FGFR isoforms in thyroid cancer progression and suggest potential therapeutic targets.

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