title: Activation of mTOR signaling in medullary and aggressive papillary thyroid carcinomas.
abstract: BACKGROUND
  Because mammalian target of rapamycin (mTOR) may be involved in thyroid carcinogenesis, we investigated the expression and activation patterns of mTOR signaling proteins in thyroid carcinoma cells and tumors and their association with tumor histology and aggressiveness.
  
  
  METHODS
  Tissue specimens from 50 patients with thyroid cancer were analyzed for eIF4E, a critical downstream target of the mTOR pathway, using immunohistochemistry. In addition, fresh-frozen samples from patients, and primary tumor cell cultures were analyzed for expression and activation of mTOR signaling proteins by Western blot. Moreover, pharmacologic studies with rapamycin were performed.
  
  
  RESULTS
  High expression of eIF4E was observed in medullary thyroid carcinomas (MTC) and in aggressive variants of papillary thyroid carcinomas (PTC) as compared with conventional PTC and follicular thyroid carcinomas (P < .0001). The level of eIF4E expression also correlated with tumor stage (P = .002). Using Western blot analysis, p-rpS6, p-4EBP1, 4EBP1, and eIF4E were detected at higher levels in aggressive PTC and MTC cells. Treatment of MTC cells with increasing concentrations of rapamycin resulted in significant cell death and in decreased cell growth associated with deactivation of the mTOR pathway.
  
  
  CONCLUSIONS
  mTOR signaling, which controls protein synthesis through regulation of translation initiation, is activated in aggressive PTC and MTC and represents a promising target for investigational therapies in these patients.
authors.affiliation: Department of Surgery, University of Thessaly, University Hospital of Larissa, Larissa, Greece.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Kouvaraki
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Liakou
authors.forename: Adriani
authors.initials: A
authors.lastname: Paraschi
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Dimas
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.forename: Sofia
authors.initials: S
authors.lastname: Tseleni-Balafouta
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Moraitis
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002277:Carcinoma; D018278:Carcinoma, Neuroendocrine; D002291:Carcinoma, Papillary; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus