Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms

Hum Pathol. 2007 Sep;38(9):1361-71. doi: 10.1016/j.humpath.2007.01.028. Epub 2007 May 22.


Angiomyolipoma (AML) belong to a family of tumors known as perivascular epithelioid cell tumors (PEComas) that share a common immunophenotypic profile of muscle and melanocytic differentiation. These tumors are clonal in nature and have a strong association with tuberous sclerosis. Genetic analyses have reported allelic imbalance at the TSC2 locus on 16p13. In the context of non-tuberous sclerosis complex (TSC), non-lymphangioleiomyomatosis-associated AMLs, and non-renal PEComas, the functional status of the TSC2 signaling pathway has not been reported. Studies over the last several years have uncovered a critical role of the TSC1/2 genes in negatively regulating the Rheb/mTOR/p70S6K cascade. Here, we examined the activity of this pathway in sporadic AMLs and PEComas using immunohistochemical and biochemical analyses. We found increased levels of phospho-p70S6K, a marker of mTOR activity, in 15 of 15 non-TSC AMLs. This was accompanied by reduced phospho-AKT expression, a pattern that is consistent with the disruption of TSC1/2 function. Western blot analysis confirmed mTOR activation concurrent with the loss of TSC2 and not TSC1 in sporadic AMLs. Similarly, elevated phospho-p70S6K and reduced phospho-AKT expression was detected in 14 of 15 cases of extrarenal PEComas. These observations provide the first functional evidence that mTOR activation is common to sporadic, non-TSC-related AMLs and PEComas. This suggests the possibility that mTOR inhibitors such as rapamycin may be therapeutic for this class of disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiomyolipoma / chemistry
  • Angiomyolipoma / metabolism
  • Angiomyolipoma / pathology*
  • Biomarkers, Tumor / analysis*
  • Blotting, Western
  • Epithelioid Cells*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Kidney Neoplasms / chemistry
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Neoplasms, Connective and Soft Tissue / chemistry
  • Neoplasms, Connective and Soft Tissue / metabolism
  • Neoplasms, Connective and Soft Tissue / pathology*
  • Oncogene Protein v-akt / analysis
  • PTEN Phosphohydrolase / metabolism
  • Protein Kinases / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / analysis
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / analysis
  • Up-Regulation


  • Biomarkers, Tumor
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Protein Kinases
  • MTOR protein, human
  • Oncogene Protein v-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase