RESUMO
BACKGROUND AND PURPOSE: Pleomorphic xanthoastrocytomas are rare astrocytic neoplasms of childhood and young adulthood. The purpose of this retrospective review was to evaluate MR imaging features of pediatric pleomorphic xanthoastrocytomas with an emphasis on diffusion MR imaging. MATERIALS AND METHODS: Review of the neuro-oncology data base revealed 11 pediatric patients (range, 4.7-16.1 years) with pleomorphic xanthoastroacytomas with 9 of these patients having preoperative MR imaging available. Six patients had preoperative diffusion MR imaging. Demographics, histopathology slides, conventional imaging characteristics (location, cystic component, hemorrhage, enhancement, vasogenic edema, inner table scalloping), and ADC metrics (mean tumor ADC and tumor to normal brain ADC ratio) were evaluated. RESULTS: Three pleomorphic xanthoastrocytomas had anaplastic features. Ten tumors were supratentorial. Two-thirds (6 of 9) of all tumors were either predominantly cystic or had cystic components, and three-fourths (6 of 8) of the supratentorial tumors had associated inner table scalloping. Seven of the 9 tumors had marked vasogenic edema (>10 mm). Mean tumoral ADC (n = 7) was 912 ± 219 × 10(-6) mm(2)/s (min-max: 617-1189). The tumor to normal brain ADC ratio was 1.14 ± 0.26 (min-max: 0.75-1.47). CONCLUSIONS: Pleomorphic xanthoastrocytoma should be entertained in the differential diagnosis of peripheral supratentorial tumors that appear during childhood. Cysts, inner table scalloping, and marked vasogenic edema are relatively frequent features. Relatively low ADC values and ADC ratios are not uncommon in pleomorphic xanthoastrocytoma.
Assuntos
Astrocitoma/patologia , Imagem de Difusão por Ressonância Magnética , Neoplasias Supratentoriais/patologia , Adolescente , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Neuroimagem , Estudos RetrospectivosRESUMO
Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.
Assuntos
Sobrevivência Celular/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios Aferentes/fisiologia , Animais , Axônios/fisiologia , Fracionamento Celular , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Gânglios Espinais/citologia , Genes Reporter/genética , Microscopia de Fluorescência , Proteína Quinase 7 Ativada por Mitógeno , Fosforilação , Transporte Proteico/fisiologia , Ratos , Receptores de Fator de Crescimento Neural/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Peripheral ganglion neurons confer sensory information including touch, pain, temperature, and proprioception. Sensory modality is linked to specific neurotrophin (NTF) requirements. NT-3 supports survival of neurons that differentiate primarily into proprioceptors whereas nerve growth factor and brain-derived neurotrophic factor (BDNF) support subpopulations that transmit nociception and mechanoreception, respectively. We examined sensory neurons of gene-targeted mouse mutants at the NT-4, BDNF, NT-3, and TrkA loci. We show that NT-4 functions early in gangliogenesis, upstream of BDNF. In the absence of NT-4 function, BDNF-dependent, TrkB-expressing neurons fail to appear. The results are consistent with the model that precursor cells intended to become BDNF-dependent mechanoreceptors instead differentiate into NT-3-dependent proprioceptive neurons.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fatores de Crescimento Neural/fisiologia , Crista Neural/citologia , Neurônios Aferentes/citologia , Animais , Apoptose , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/genética , Contagem de Células , Gânglios Espinais/citologia , Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fatores de Crescimento Neural/genética , Receptor trkB/biossínteseRESUMO
The mechanisms underlying neuronal ischemic preconditioning, a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia, are poorly understood. Ischemia can be modeled in vitro by oxygen-glucose deprivation (OGD). We report here that OGD preconditioning induces p21(ras) (Ras) activation in an N-methyl-D-aspartate receptor- and NO-dependent, but cGMP-independent, manner. We demonstrate that Ras activity is necessary and sufficient for OGD tolerance in neurons. Pharmacological inhibition of Ras, as well as a dominant negative mutant Ras, block OGD preconditioning whereas a constitutively active form of Ras promotes neuroprotection against lethal OGD insults. In contrast, the activity of phosphatidyl inositol 3-kinase is not required for OGD preconditioning because inhibition of phosphatidyl inositol 3-kinase with a chemical inhibitor or with a dominant negative mutant does not have any effect on the development of OGD tolerance. Furthermore, using recombinant adenoviruses and pharmacological inhibitors, we show that downstream of Ras the extracellular regulated kinase cascade is required for OGD preconditioning. Our observations indicate that activation of the Ras/extracellular regulated kinase cascade by NO is a critical mechanism for the development of OGD tolerance in cortical neurons, which may also play an important role in ischemic preconditioning in vivo.
Assuntos
Precondicionamento Isquêmico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenoviridae/metabolismo , Anaerobiose , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Células Cultivadas , Cromonas/farmacologia , Glucose/deficiência , Morfolinas/farmacologia , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Simplexvirus/genética , TransfecçãoRESUMO
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by increased incidence of benign and malignant tumors of neural crest origin. Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate with inactivating mutations at the p53 tumor suppressor gene during malignant transformation. One hundred percent of mice harboring null Nf1 and p53 alleles in cis synergize to develop soft tissue sarcomas between 3 and 7 months of age. These sarcomas exhibit loss of heterozygosity at both gene loci and express phenotypic traits characteristic of neural crest derivatives and human NF1 malignancies.
Assuntos
Modelos Animais de Doenças , Genes da Neurofibromatose 1 , Genes p53 , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Sarcoma/patologia , Animais , Biomarcadores Tumorais , Diferenciação Celular , Transformação Celular Neoplásica , Cruzamentos Genéticos , Feminino , Heterozigoto , Humanos , Perda de Heterozigosidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Crista Neural/metabolismo , Crista Neural/patologia , Sarcoma/genética , Células de Schwann/metabolismo , Células de Schwann/patologia , Células Tumorais CultivadasRESUMO
The neurotrophin family of growth factors supports survival and differentiation of neurons in the developing vertebrate nervous system by binding activating receptor tyrosine kinases, the Trks. Activation of Trk receptors leads to stimulation of a number of intracellular signaling cascades including, among others, the ras/extracellular regulated kinase (erk) and the phosphatidylinositol-3 kinase (PI 3 kinase) cascades. Over the past several years, work in several neurotrophin responsive systems has begun to identify the role each of these signaling cascades plays in the cellular response to neurotrophins. It now appears that neurotrophins, in particular nerve growth factor (NGF), mediate their multiple effects through a number of distinct intracellular signaling cascades. In this review, we will overview the evidence implicating specific signaling cascades in aspects of the cellular response to the neurotrophins, specifically in response to activation of TrkA by NGF.
Assuntos
Fatores de Crescimento Neural/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores de Fator de Crescimento Neural/fisiologia , Transdução de Sinais/fisiologia , Animais , Diferenciação Celular/fisiologia , Sobrevivência Celular/fisiologia , Genes ras/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/metabolismo , Células PC12/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Receptor trkARESUMO
Nerve growth factor induces differentiation and survival of rat PC12 pheochromocytoma cells. The activation of the erk cascade has been implicated in transducing the multitude of signals induced by NGF. In order to explore the role of this signaling cascade in NGF mediated survival, differentiation and proliferation, we generated recombinant adenoviruses which express the intermediates of the erk cascade in their wild type, dominant negative and constitutively activated forms. We show that differentiation of PC12 cells requires activity of the ras/erk pathway, whereas inhibition of this pathway had no effect on survival or proliferation. Constitutively active forms of ras, raf and mek induced PC12 cell differentiation, while dominant interfering forms inhibited differentiation. Survival of PC12 cells in serum-free medium did not require activity of the ras/erk pathway. Instead, PI3 Kinase signaling was necessary for PC12 cell survival. Interestingly, constitutively activated versions of raf and mek were able to promote survival, but again this was dependent on activation of PI3 Kinase. Therefore, at least two distinct signaling pathways are required in PC12 cells for mediation of NGF functions.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Fatores de Crescimento Neural/farmacologia , Neurônios/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Diferenciação Celular , Divisão Celular , Sobrevivência Celular , Células PC12 , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Sistema Nervoso Simpático/citologiaRESUMO
Insulin receptor-related receptor (IRR), an orphan receptor in the insulin receptor (IR) family of receptor tyrosine kinases, is primarily localized to neural crest-derived sensory neurons during embryonic development. Expression of IRR closely resembles that of the nerve growth factor receptor, TrkA. To analyze the signaling properties and function of IRR in PC12 cells, a TrkB/IRR hybrid receptor was used. In contrast to IR activation, brain-derived neurotrophic growth factor-mediated activation of the TrkB/IRR receptor resulted in differentiation rather than proliferation. Analysis of cytoplasmic substrates activated by the TrkB/IRR receptor indicates a signaling pathway similar to that of the IR. Mutagenesis studies further show that only TrkB/IRR receptors able to phosphorylate mitogen-activated protein kinase elicit a differentiation response. Our analysis indicates that prolonged kinetics of mitogen-activated protein kinase activation mediated by the TrkB/IRR chimeric receptor correlates with induction to differentiate.
Assuntos
Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptor de Insulina/metabolismo , Receptor trkB/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Diferenciação Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Cinética , Células PC12/citologia , Células PC12/efeitos dos fármacos , Ratos , Receptor de Insulina/genética , Receptor trkB/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Especificidade por Substrato , Tirosina/metabolismoRESUMO
Nerve growth factor (NGF) is a required differentiation and survival factor for sympathetic and a majority of neural crest-derived sensory neurons in the developing vertebrate peripheral nervous system. Although much is known about the function of NGF, the intracellular signaling cascade that it uses continues to be a subject of intense study. p21 ras signaling is considered necessary for sensory neuron survival. How additional intermediates downstream or in parallel may function has not been fully understood yet. Two intracellular signaling cascades, extra cellular regulated kinase (erk) and phosphatidylinositol-3 (PI 3) kinase, transduce NGF signaling in the pheochromocytoma cell line PC12. To elucidate the role these cascades play in survival and differentiation, we used a combination of recombinant adenoviruses and chemical inhibitors to perturb these pathways in sensory neurons from wild-type mice and mice deficient for neurofibromin in which the survival and differentiation pathway is constitutively active. We demonstrate that ras activity is both necessary and sufficient for the survival of embryonic sensory neurons. Downstream of ras, however, the erk cascade is neither required nor sufficient for neuron survival or overall differentiation. Instead, the activity of PI 3 kinase is necessary for the survival of the wild-type and neurofibromin-deficient neurons. Therefore, we conclude that in sensory neurons, NGF acts via a signaling pathway, which includes both ras and PI 3 kinase.