title: BRAF(V600E) mutation and expression of proangiogenic molecular markers in papillary thyroid carcinomas.
abstract: OBJECTIVE
  Tyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear.
  
  
  METHODS
  The aim of our study was to investigate the impact of BRAF(V600E) on proangiogenic gene expression and microvascular features of PTCs.
  
  
  METHODS
  mRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin-1), and PDGF receptor β (PDGFRβ or PDGFRB) were measured with real-time PCR in BRAF(V600E) (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAF(V600E) cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAF(V600E) mutation in thyrocyte lines.
  
  
  RESULTS
  Transcript levels of proangiogenic factors were significantly lower in BRAF(V600E) PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAF(V600E) mutation was induced (P=0.01) and increased when it was silenced (P=0.01).
  
  
  CONCLUSIONS
  Compared with BRAF-wt PTCs, those harboring BRAF(V600E) exhibit downregulated VEGFA, VEGFR, and PDGFRβ expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways.
authors.affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma Sapienza, V.le del Policlinico, 155, 00161 Roma, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: Efisio
authors.initials: E
authors.lastname: Puxeddu
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.forename: Sonia
authors.initials: S
authors.lastname: Moretti
authors.forename: Claudia
authors.initials: C
authors.lastname: Ligorio
authors.forename: Antonio
authors.initials: A
authors.lastname: Cavaliere
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Rhoden
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.forename: Marianna
authors.initials: M
authors.lastname: Maranghi
authors.forename: Laura
authors.initials: L
authors.lastname: Giacomelli
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000096:biosynthesis*; D002277:Carcinoma; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D042501:Angiogenic Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf