Morphoproteomics demonstrates activation of mammalian target of rapamycin pathway in papillary thyroid carcinomas with nuclear translocation of MTOR in aggressive histological variants

Mod Pathol. 2011 Dec;24(12):1553-9. doi: 10.1038/modpathol.2011.121. Epub 2011 Aug 5.

Abstract

We used morphoproteomics to investigate mammalian target of rapamycin (MTOR) signaling pathway in papillary thyroid carcinomas and correlated the results with clinicopathological parameters. Archival paraffin-embedded tissue of papillary thyroid carcinomas was obtained from 30 patients, including 15 classical type and 8 follicular, 4 tall-cell, 1 columnar-cell, 1 diffuse sclerosing and 1 cribriform variants. Immunohistochemical stains were performed for three phosphorylated (p) protein analytes: p-MTOR (Ser2448), p-Akt (Ser473) and p-p70S6K (Thr389). Chromogenic signals and subcellular compartmentalization (nuclear, cytoplasmic and plasmalemmal) were evaluated. Clinicopathological parameters were reviewed. Immunoreactivities for p-MTOR, p-Akt and p-p70S6K were observed in all papillary thyroid carcinomas. In addition to an expression of p-MTOR in cytoplasmic location, nuclear translocation of p-MTOR with variable loss of plasmalemmal expression, and with concomitant nuclear expression of p-Akt, was also identified in all tall-cell, columnar-cell and diffuse sclerosing variants of papillary thyroid carcinoma. There were no significant differences in the clinicopathological parameters, including tumor size, extrathyroidal extension, angioinvasion and nodal metastases between the groups with and without nuclear expression of p-MTOR (P>0.05). The expressions of p-MTOR in cytoplasmic and/or plasmalemmal locations with the concomitant immunoreactivity for p-p70S6K in all papillary thyroid carcinomas indicate the activation of MTOR complex 1 pathway. The nuclear translocation of p-MTOR evidences the activation of MTOR complex 2 and is identified only in the known aggressive histological variants of papillary thyroid carcinoma, including tall-cell, columnar-cell and diffuse sclerosing variants. Thus, these results suggest the constitutive activation of MTOR signaling pathway in papillary thyroid carcinomas and provide a new insight of biogenetic basis for the aggressive histological variants of papillary thyroid carcinoma. The pattern of expression of p-MTOR in papillary thyroid carcinomas may serve as a diagnostic/prognostic marker and a potential therapeutic target.

MeSH terms

  • Active Transport, Cell Nucleus
  • Biomarkers, Tumor / analysis*
  • Carcinoma
  • Carcinoma, Papillary
  • Cell Nucleus / enzymology*
  • Cell Nucleus / pathology
  • Enzyme Activation
  • Humans
  • Immunohistochemistry
  • Lymphatic Metastasis
  • Neoplasm Invasiveness
  • Phosphorylation
  • Prognosis
  • Proteomics* / methods
  • Proto-Oncogene Proteins c-akt / analysis
  • Ribosomal Protein S6 Kinases, 70-kDa / analysis
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / analysis*
  • Thyroid Cancer, Papillary
  • Thyroid Neoplasms / enzymology*
  • Thyroid Neoplasms / secondary
  • Tumor Burden

Substances

  • Biomarkers, Tumor
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa