title: Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms.
abstract: 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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kenerson
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Folpe
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Takayama
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Yeung
mesh_terms: D018207:Angiomyolipoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D015622:Epithelioid Cells; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D018204:Neoplasms, Connective and Soft Tissue / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000032:analysis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000032:analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase