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Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to

Nami Sugiyama1, Markku Varjosalo, Pipsa Meller

  • 1Molecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, Helsinki, Finland.

Cancer Research
|September 30, 2010
PubMed

Insights

The FGFR4-R388 gene variant promotes cancer progression by increasing matrix degradation and invasion, while the FGFR4-G388 allele has the opposite effect. This explains the link between FGFR4-R388 and poor cancer prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Aberrant fibroblast growth factor receptor 4 (FGFR4) expression and genetic variations are implicated in tumor progression and resistance to cancer therapies.
  • The FGFR4-R388 risk variant is associated with poor cancer prognosis.
  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a role in extracellular matrix degradation and tumor invasion.

Purpose of the Study:

  • To elucidate a novel mechanism of tumor progression involving matrix degradation and epithelial-to-mesenchymal transition.
  • To investigate the role of the FGFR4-R388 variant in MT1-MMP induction and tumor cell invasion.
  • To explore the impact of FGFR4 variants on cancer cell behavior and prognosis.

Main Methods:

  • Analysis of FGFR4 and MT1-MMP expression in human cancer biopsies (breast, prostate).
  • In vitro studies using cultured prostate carcinoma cell lines with FGFR4-R388 and FGFR4-G388 variants.
  • RNA interference (RNAi) to knockdown FGFR4-R388, FGFR4-G388, or MT1-MMP.
  • Assessment of tumor cell invasion, growth, and molecular signaling pathways (FGFR substrate 2, Src, cadherins).
  • In vivo studies to evaluate tumor growth and MT1-MMP content after gene silencing.

Main Results:

  • FGFR4 and MT1-MMP were upregulated and coexpressed at invasive fronts in various human cancers, notably prostate carcinoma.
  • The FGFR4-R388 variant enhanced MT1-MMP-dependent collagen invasion and tumor growth.
  • Knockdown of FGFR4-R388 or MT1-MMP inhibited tumor cell invasion and growth, with associated molecular changes (e.g., E-cadherin upregulation).
  • Conversely, knockdown of the FGFR4-G388 allele increased MT1-MMP and invasive tumor cell growth.

Conclusions:

  • The FGFR4-R388 variant drives tumor progression through MT1-MMP induction and matrix degradation, contributing to poor prognosis.
  • FGFR4-R388 and MT1-MMP are key players in cancer cell invasion and growth.
  • Understanding the differential roles of FGFR4 alleles (R388 vs. G388) provides insights into cancer progression mechanisms and potential therapeutic targets.

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