title: Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases.
abstract: OBJECTIVE
  Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease.
  
  
  METHODS
  We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade.
  
  
  RESULTS
  Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells.
  
  
  CONCLUSIONS
  The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC.
authors: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors: Anna
authors: A
authors: Tamburrino
authors: Alfredo A
authors: AA
authors: Molinolo
authors: Paolo
authors: P
authors: Salerno
authors: Rebecca D
authors: RD
authors: Chernock
authors: Mark
authors: M
authors: Raffeld
authors: Liqiang
authors: L
authors: Xi
authors: J Silvio
authors: JS
authors: Gutkind
authors: Jeffrey F
authors: JF
authors: Moley
authors: Samuel A
authors: SA
authors: Wells
authors: Massimo
authors: M
authors: Santoro
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013952:Thymus Hyperplasia / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C546842:MTOR protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus