RESUMO
Gliomas with Isocitrate dehydrogenase 1 (IDH1) mutation have alterations in several enzyme activities, resulting in various metabolic changes. The aim of this study was to determine a mechanism for the better prognosis of gliomas with IDH mutation by performing metabolomic analysis. To understand the metabolic state of human gliomas, we analyzed clinical samples obtained from surgical resection of glioma patients (grades II-IV) with or without the IDH1 mutation, and compared the results with U87 glioblastoma cells overexpressing IDH1 or IDH1R132H. In clinical samples of gliomas with IDH1 mutation, levels of D-2-hydroxyglutarate (D-2HG) were increased significantly compared with gliomas without IDH mutation. Gliomas with IDH mutation also showed decreased intermediates in the tricarboxylic acid cycle and pathways involved in the production of energy, amino acids, and nucleic acids. The marked difference in the metabolic profile in IDH mutant clinical glioma samples compared with that of mutant IDH expressing cells includes a decrease in ß-oxidation due to acyl-carnitine and carnitine deficiencies. These metabolic changes may explain the lower cell division rate observed in IDH mutant gliomas and may provide a better prognosis in IDH mutant gliomas.
Assuntos
Neoplasias Encefálicas/metabolismo , Carnitina/análogos & derivados , Glioblastoma/metabolismo , Isocitrato Desidrogenase/genética , Metabolômica/métodos , Adulto , Idoso , Biomarcadores Tumorais/deficiência , Neoplasias Encefálicas/patologia , Carnitina/deficiência , Divisão Celular/genética , Linhagem Celular Tumoral , Feminino , Glioblastoma/patologia , Glutaratos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Oxirredução , Prognóstico , Transdução de Sinais/genética , TransfecçãoRESUMO
We report the case of a 59-year-old women with a cerebral arteriovenous malformation (AVM) in the right frontal lobe, which was detected incidentally. Additionally, an aneurysm was found at the feeding artery of the AVM. The patient was treated conservatively. Nine years later, the nidus of the AVM was no longer detectable. The angiography showed the associated aneurysm growing irregularly with a daughter sac. The spontaneous occlusion of an AVM and the following progression of an associated aneurysm are rare. The possible mechanisms leading to the occlusion of the AVM and the progression of the associated aneurysm are discussed.
Assuntos
Lobo Frontal/irrigação sanguínea , Aneurisma Intracraniano/complicações , Malformações Arteriovenosas Intracranianas/complicações , Angiografia Cerebral , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Feminino , Humanos , Achados Incidentais , Aneurisma Intracraniano/diagnóstico , Aneurisma Intracraniano/fisiopatologia , Aneurisma Intracraniano/terapia , Malformações Arteriovenosas Intracranianas/diagnóstico , Malformações Arteriovenosas Intracranianas/fisiopatologia , Malformações Arteriovenosas Intracranianas/terapia , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Cytosolic isocitrate dehydrogenase 1 (IDH1) with an R132H mutation in brain tumors loses its enzymatic activity for catalyzing isocitrate to α-ketoglutarate (α-KG) and acquires new activity whereby it converts α-KG to 2-hydroxyglutarate. The IDH1 mutation induces down-regulation of tricarboxylic acid cycle intermediates and up-regulation of lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) regulate not only the synthesis of cholesterol and fatty acids but also acyclin-dependent kinase inhibitor p21 that halts the cell cycle at G1. Here we show that SREBPs were up-regulated in U87 human glioblastoma cells transfected with an IDH1(R132H)-expression plasmid. Small interfering ribonucleic acid (siRNA) for SREBP1 specifically decreased p21 messenger RNA (mRNA) levels independent of the p53 pathway. In IDH1(R132H)-expressing U87 cells, phosphorylation of Retinoblastoma (Rb) protein also decreased. We propose that metabolic changes induced by the IDH1 mutation enhance p21 expression via SREBP1 and inhibit phosphorylation of Rb, which slows progression of the cell cycle and may be associated with non-aggressive features of gliomas with an IDH1 mutation.
Assuntos
Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Isocitrato Desidrogenase/fisiologia , Mutação de Sentido Incorreto , Proteínas de Neoplasias/fisiologia , Mutação Puntual , Processamento de Proteína Pós-Traducional , Substituição de Aminoácidos , Neoplasias Encefálicas/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Glioblastoma/metabolismo , Humanos , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/genética , Metabolismo dos Lipídeos , Mutagênese Sítio-Dirigida , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Fosforilação , Interferência de RNA , Proteínas Recombinantes de Fusão/metabolismo , Proteína do Retinoblastoma/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Transfecção , Regulação para CimaRESUMO
A case of unclassified, pediatric cerebral neuroepithelial tumor in a 10-year-old girl that showed remarkable radiosensitivity is reported. MRI revealed a brain tumor of mixed intensity with heterogeneous enhancement in the medial temporal lobe, extending to the basal ganglia. The tumor was partially removed. On pathology, the main part of the tumor showed immature features: the tumor cells had a chromatin-rich large nucleus and less cytoplasm, and mitoses and fragmentation of the nuclei were frequent. On immunohistochemistry, the tumor cells were negative for glial fibrillary acidic protein (GFAP) and synaptophysin and positive for Olig2. The maximum MIB-1 index was 70%. The part invading into the surrounding brain showed similarities in form to a highly anaplastic astrocytoma. The infiltrating tumor cells were positive for GFAP and less positive for Olig2. After 40 Gy radiation, the residual tumor was markedly reduced. Neuroepithelial tumors rarely show such high radiosensitivity, and the reason for the radiosensitivity in the present case may have been the immaturity of the tumor cells.
