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BRAF(V600E) mutation and expression of proangiogenic molecular markers in papillary thyroid carcinomas

Cosimo Durante1, Giovanni Tallini, Efisio Puxeddu

  • 1Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma Sapienza, V.le del Policlinico, 155, 00161 Roma, Italy.

European Journal of Endocrinology
|June 10, 2011
PubMed
Abstract

Insights

The BRAF(V600E) mutation in papillary thyroid cancer is associated with lower expression of proangiogenic factors like VEGFA, VEGFR, and PDGFRβ. This suggests BRAF mutation status may not predict response to anti-VEGF/PDGF therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Tyrosine kinase inhibitors (TKIs) are used for radioiodine-refractory thyroid cancer, targeting proangiogenic signaling pathways.
  • BRAF mutations, particularly BRAF(V600E), are common in papillary thyroid cancer (PTC) but their impact on these pathways is unclear.

Purpose of the Study:

  • To investigate the effect of the BRAF(V600E) mutation on proangiogenic gene expression and microvascular characteristics in PTC.
  • To determine if BRAF(V600E) influences the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) pathway components.

Main Methods:

  • Real-time PCR was used to quantify mRNA levels of VEGFA, VEGFRs, and PDGFRβ in PTCs with BRAF(V600E) (n=55) and wild-type BRAF (BRAF-wt; n=35).
  • Immunohistochemistry assessed VEGF and VEGFR protein expression, and microvessel and lymphatic vessel densities in a subset of samples.
  • In vitro experiments involved inducing or silencing the BRAF(V600E) mutation in thyrocyte cell lines to study angiogenic gene expression.

Main Results:

  • Transcript levels of proangiogenic factors were significantly lower in BRAF(V600E) PTCs compared to BRAF-wt PTCs (P<0.0001).
  • Microvessel density (MVD) and lymphatic vessel density (LVD) did not show significant differences between the groups.
  • VEGFA mRNA levels decreased upon BRAF(V600E) induction and increased upon its silencing in cell lines (P=0.01 for both).

Conclusions:

  • Papillary thyroid cancers with the BRAF(V600E) mutation exhibit downregulated expression of VEGFA, VEGFR, and PDGFRβ compared to BRAF-wt tumors.
  • The presence of the BRAF(V600E) mutation does not appear to be a strong predictor of response to therapies targeting VEGF and PDGF signaling pathways.

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