title: Targeting epidermal growth factor receptor 1 signaling in human thyroid-stimulating hormone-independent thyroid carcinoma FRO cells results in a more chemosensitive and less angiogenic phenotype.
abstract: BACKGROUND
  Poorly differentiated and anaplastic thyroid cancers are aggressive malignancies unresponsive to standard treatments. The mechanisms responsible for the progression of thyroid tumors toward a thyroid-stimulating hormone (TSH)-independent phenotype are still under discussion, and a better understanding of them may provide novel molecular targets for the treatment of this disease. We evaluated the hypothesis that epithelial growth factor (EGF) signaling may play a role in favoring the loss of TSH dependency in human differentiated thyroid tumor cells.
  
  
  METHODS
  The sensitivity to EGF stimulation was evaluated in follicular thyroid carcinoma WRO cells that retain some features of thyroid cell differentiation and in undifferentiated TSH-independent thyroid carcinoma FRO cells.
  
  
  RESULTS
  It was observed that, while both cell lines are characterized by a similar EGF-dependent activation of the RAS/MAPK signaling pathway, only FRO cells exhibited a significant induction of phosphoAKT, cell proliferation, and migration as well as the up-regulation of vascular endothelial growth factor-A expression in response to EGF. On the other hand, the inhibition of epidermal growth factor receptor 1 signaling by its tyrosine kinase inhibitor, erlotinib, caused a selective down-regulation of FRO cell proliferation and induced a phenotype more sensitive to the proapoptotic activity of anthracyclins and taxoids. By contrast, the protracted stimulation of TSH-dependent WRO cells with EGF induced the loss of TSH dependency and the rearrangement of F-actin cytoskeleton.
  
  
  CONCLUSIONS
  These results suggest that the acquired sensitivity to EGF in these thyroid tumor cells may be responsible for the loss of differentiation in the transition toward a TSH-independent, invasive, and chemoresistant phenotype.
authors.affiliation: Department of Medical Sciences, University of Foggia, Foggia, Italy. m.landriscina@unifg.it
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
authors.forename: Annamaria
authors.initials: A
authors.lastname: Piscazzi
authors.forename: Annarita
authors.initials: A
authors.lastname: Fabiano
authors.forename: Francesca
authors.initials: F
authors.lastname: Maddalena
authors.forename: Eleonora
authors.initials: E
authors.lastname: Costantino
authors.forename: Anna
authors.initials: A
authors.lastname: Farese
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Bufo
authors.forename: Mauro
authors.initials: M
authors.lastname: Cignarelli
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010641:Phenotype; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013972:Thyrotropin / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D013778:Tetrazolium Salts; D013844:Thiazoles; D013972:Thyrotropin; D066246:ErbB Receptors; C022616:thiazolyl blue