Frequent [corrected] hyperphosphorylation of ribosomal protein S6 [corrected] in lymphangioleiomyomatosis-associated angiomyolipomas.
Lymphangioleiomyomatosis is a progressive lung disease characterized by a diffuse proliferation of pulmonary smooth muscle cells and cystic degeneration. Lymphangioleiomyomatosis can occur either independently of other disease or in association with tuberous sclerosis complex, a tumor-suppressor gene syndrome caused by mutations that inactivate either TSC1 or TSC2. TSC2 mutations and loss of heterozygosity have been identified in sporadic lymphangioleiomyomatosis-associated angiomyolipomas, thus implicating the TSC/Ras homolog-enriched in brain (Rheb)/mammalian target of Rapamycin (mTOR)/p70 S6 kinase signaling pathway in their pathogenesis. This study was undertaken to determine whether the mTOR/p70 S6 kinase signaling pathway is activated in lymphangioleiomyomatosis-associated angiomyolipomas lacking TSC1/TSC2 loss of heterozygosity. Phospho-ribosomal protein S6 (Ser235/236) immunohistochemistry was performed on five lymphangioleiomyomatosis-associated angiomyolipomas, two matched lymphangioleiomyomatosis pulmonary samples, and three sporadic angiomyolipomas. TSC1/TSC2 loss of heterozygosity was previously excluded in these angiomyolipomas. Moderate or strong phospho-ribosomal protein S6 immunoreactivity was found in all lymphangioleiomyomatosis-associated and sporadic angiomyolipomas, suggesting a high incidence of mTOR/p70 S6 kinase signaling pathway activation despite a lack of TSC1/TSC2 loss of heterozygosity. Focally positive phospho-S6 staining was also evident in both lymphangioleiomyomatosis pulmonary samples. We hypothesized that this S6 hyperphosphorylation could reflect mutational activation of Rheb or Rheb-like protein (RhebL1), Ras family members which directly activate mTOR. Mutational analysis performed on DNA from these eight angiomyolipomas plus five additional sporadic angiomyolipomas did not reveal mutations in exons 3 and 4 (homologous sites of Ras activating mutations) of either Rheb or RhebL1. These data suggest that activation of the Rheb/mTOR/p70 S6 kinase pathway is related to the pathogenesis of lymphangioleiomyomatosis-associated and sporadic angiomyolipomas lacking TSC1/TSC2 loss of heterozygosity. This high incidence of mTOR signaling pathway activation suggests that treatment with mTOR inhibitors, such as Rapamycin, may benefit patients with angiomyolipomas independent of the detection of TSC1/TSC2 loss of heterozygosity.
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Victoria A
VA
Robb
Aristotelis
A
Astrinidis
Elizabeth P
EP
Henske
D018207:Angiomyolipoma / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000378:metabolism* / Q000473:pathology; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009378:Neoplasms, Multiple Primary; D009479:Neuropeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D000076205:Ras Homolog Enriched in Brain Protein; D038601:Ribosomal Protein S6; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C490211:RHEB protein, human; C504241:RHEBL1 protein, human; C546842:MTOR protein, human