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1.
Acta Neuropathol ; 131(6): 803-20, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27157931

RESUMEN

The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.


Asunto(s)
Encéfalo/patología , Neoplasias del Sistema Nervioso Central/clasificación , Sistema Nervioso Central/patología , Glioma/clasificación , Meningioma/clasificación , Organización Mundial de la Salud , Animales , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/patología , Glioma/patología , Humanos , Meningioma/diagnóstico , Meningioma/patología
2.
Acta Neuropathol ; 125(5): 651-8, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23575898

RESUMEN

Non-central nervous system hemangiopericytoma (HPC) and solitary fibrous tumor (SFT) are considered by pathologists as two variants of a single tumor entity now subsumed under the entity SFT. Recent detection of frequent NAB2-STAT6 fusions in both, HPC and SFT, provided additional support for this view. On the other hand, current neuropathological practice still distinguishes between HPC and SFT. The present study set out to identify genes involved in the formation of meningeal HPC. We performed exome sequencing and detected the NAB2-STAT6 fusion in DNA of 8/10 meningeal HPC thereby providing evidence of close relationship of these tumors with peripheral SFT. Due to the considerable effort required for exome sequencing, we sought to explore surrogate markers for the NAB2-STAT6 fusion protein. We adopted the Duolink proximity ligation assay and demonstrated the presence of NAB2-STAT6 fusion protein in 17/17 HPC and the absence in 15/15 meningiomas. More practical, presence of the NAB2-STAT6 fusion protein resulted in a strong nuclear signal in STAT6 immunohistochemistry. The nuclear reallocation of STAT6 was detected in 35/37 meningeal HPC and 25/25 meningeal SFT but not in 87 meningiomas representing the most important differential diagnosis. Tissues not harboring the NAB2-STAT6 fusion protein presented with nuclear expression of NAB2 and cytoplasmic expression of STAT6 proteins. In conclusion, we provide strong evidence for meningeal HPC and SFT to constitute variants of a single entity which is defined by NAB2-STAT6 fusion. In addition, we demonstrate that this fusion can be rapidly detected by STAT6 immunohistochemistry which shows a consistent nuclear reallocation. This immunohistochemical assay may prove valuable for the differentiation of HPC and SFT from other mesenchymal neoplasms.


Asunto(s)
Hemangiopericitoma/genética , Neoplasias Meníngeas/genética , Proteínas de Fusión Oncogénica/fisiología , Proteínas Represoras/fisiología , Factor de Transcripción STAT6/fisiología , Tumores Fibrosos Solitarios/genética , Estudios de Cohortes , Diagnóstico Diferencial , Exoma , Hemangiopericitoma/diagnóstico , Hemangiopericitoma/metabolismo , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/metabolismo , ARN Mensajero/metabolismo , Tumores Fibrosos Solitarios/diagnóstico , Tumores Fibrosos Solitarios/metabolismo
3.
Acta Neuropathol ; 125(3): 351-8, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23404370

RESUMEN

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.


Asunto(s)
Factores de Transcripción de Tipo Kruppel/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Mutación/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Análisis Mutacional de ADN , Genómica , Glutamina/genética , Humanos , Factor 4 Similar a Kruppel , Lisina/genética , Meningioma/patología , Polimorfismo de Nucleótido Simple/genética
4.
Nat Commun ; 13(1): 2558, 2022 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-35538064

RESUMEN

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations.


Asunto(s)
Neoplasias del Sistema Nervioso Central , Infecciones por Virus de Epstein-Barr , Linfoma de Células B Grandes Difuso , Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Genómica , Herpesvirus Humano 4 , Humanos , Linfoma de Células B Grandes Difuso/metabolismo
5.
Int J Cancer ; 128(5): 1095-103, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-20473936

RESUMEN

To identify novel glioma-associated pathomechanisms and molecular markers, we performed an array-based comparative genomic hybridization analysis of 131 diffuse astrocytic gliomas, including 87 primary glioblastomas (pGBIV), 13 secondary glioblastomas (sGBIV), 19 anaplastic astrocytomas (AAIII) and 12 diffuse astrocytomas (AII). All tumors were additionally screened for IDH1 and IDH2 mutations. Expression profiling was performed for 74 tumors (42 pGBIV, 11 sGBIV, 13 AAIII, 8 AII). Unsupervised and supervised bioinformatic analyses revealed distinct genomic and expression profiles separating pGBIV from the other entities. Classifier expression signatures were strongly associated with the IDH1 gene mutation status. Within pGBIV, the rare subtype of IDH1 mutant tumors shared expression profiles with IDH1 mutant sGBIV and was associated with longer overall survival compared with IDH1 wild-type tumors. In patients with IDH1 wild-type pGBIV, PDGFRA gain or amplification as well as 19q gain were associated with patient outcome. Array-CGH analysis additionally revealed homozygous deletions of the FGFR2 gene at 10q26.13 in 2 pGBIV, with reduced FGFR2 mRNA levels being frequent in pGBIV and linked to poor outcome. In conclusion, we report that diffuse astrocytic gliomas can be separated into 2 major molecular groups with distinct genomic and mRNA profiles as well as IDH1 gene mutation status. In addition, our results suggest FGFR2 as a novel glioma-associated candidate tumor suppressor gene on the long arm of chromosome 10.


Asunto(s)
Astrocitos/patología , Glioma/clasificación , Isocitrato Deshidrogenasa/genética , Mutación , Eliminación de Gen , Glioma/enzimología , Glioma/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Análisis de Supervivencia
6.
Acta Neuropathol ; 120(4): 529-35, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20544211

RESUMEN

Primary CNS lymphoma (PCNSL), the intracerebral subgroup of diffuse large B cell lymphoma (DLBCL), shows evidence for aberrant activation of the nuclear factor (NF)-kappaB pathway. In order to identify potential activators of the NF-kappaB complex, we analyzed the CARD11 and TNFAIP3 genes for the presence of somatic mutations and TNFAIP3 for aberrant promoter methylation in PCNSL. We also compared PCNSL to spinal DLBCL, because CARD11 and TNFAIP3 mutations have been described in systemic DLBCL. CARD11 mutations, located in the coiled-coil region, which may activate NF-kappaB, were detected in 16% (5/32) of PCNSL, while TNFAIP3 mutations were detected in 3% (1/32) of PCNSL. In PCNSL, all CARD11 mutations were heterozygous, in-frame, induced amino acid exchanges, and presumably led to activation of this oncogene. Spinal DLBCL harbored mutations of CARD11 and TNFAIP3 in 10% (1/10) and 20% (2/10) of cases, respectively. In both PCNSL and spinal DLBCL, mutations in CARD11 and TNFAIP3 were mutually exclusive. TNFAIP3 was unmethylated in all PCNSLs (30/30) and spinal DLBCLs (10/10). We conclude that mutations of the oncogene CARD11 may contribute to NF-kappaB activation and thereby play a role in the pathogenesis of PCNSL, while, in contrast to systemic DLBCL, inactivation of TNFAIP3 either by mutation or methylation seems to be of minor significance.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Neoplasias del Sistema Nervioso Central/enzimología , Guanilato Ciclasa/genética , Linfoma/enzimología , Mutación/genética , FN-kappa B/metabolismo , Transducción de Señal/genética , Adulto , Anciano , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Linfoma/genética , Masculino , Persona de Mediana Edad , Proteínas/genética , Adulto Joven
7.
Acta Neuropathol ; 120(2): 253-60, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20407781

RESUMEN

Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors (n = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80-100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior.


Asunto(s)
Cromosomas Humanos Par 19/genética , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/genética , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/genética , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Lactante , Masculino , Neoplasias de Células Germinales y Embrionarias/mortalidad , Neoplasias de Células Germinales y Embrionarias/cirugía , Tumores Neuroectodérmicos Primitivos/mortalidad , Tumores Neuroectodérmicos Primitivos/cirugía , Análisis de Supervivencia
8.
J Neuropathol Exp Neurol ; 68(9): 972-6, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19680146

RESUMEN

Forkhead box P1 (FOXP1) protein is a transcription factor involved in cell signaling and regulation of gene expression. The overexpression of FOXP1 in a subgroup of systemic diffuse large B-cell lymphomas has been associated with an exceptionally poor clinical outcome. Data on FOXP1 expression in primary central nervous system lymphomas (PCNSL), that is, diffuse large B-cell lymphomas confined to the central nervous system, are not yet available. We analyzed 43 PCNSL from immunocompetent patients. Immunohistochemistry showed expression of FOXP1 protein in 21 (88%) of 24 cases. All 19 PCNSL analyzed by quantitative gene expression analysis showed overexpression of truncated FOXP1 Isoforms 3 and 9 and downregulation of normal-size FOXP1 compared with nonmalignant germinal center B cells, the normal counterpart of PCNSL tumor cells. Thus, truncated FOXP1 isoforms are preferentially overexpressed in PCNSL as they are in diffuse large B-cell lymphomas. Although the mechanisms are presently unclear, this overexpression may contribute to a poor prognosis in PCNSL.


Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Proteínas Represoras/genética , Anciano , Western Blotting , Neoplasias del Sistema Nervioso Central/metabolismo , Femenino , Factores de Transcripción Forkhead/biosíntesis , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Isoformas de Proteínas , Proteínas Represoras/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
9.
BMC Cancer ; 9: 455, 2009 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-20025734

RESUMEN

BACKGROUND: Although primary lymphomas of the central nervous system (PCNSL) and extracerebral diffuse large B-cell lymphoma (DLBCL) cannot be distinguished histologically, it is still a matter of debate whether PCNSL differ from systemic DLBCL with respect to their molecular features and pathogenesis. Analysis of the DNA methylation pattern might provide further data distinguishing these entities at a molecular level. METHODS: Using an array-based technology we have assessed the DNA methylation status of 1,505 individual CpG loci in five PCNSL and compared the results to DNA methylation profiles of 49 DLBCL and ten hematopoietic controls. RESULTS: We identified 194 genes differentially methylated between PCNSL and normal controls. Interestingly, Polycomb target genes and genes with promoters showing a high CpG content were significantly enriched in the group of genes hypermethylated in PCNSL. However, PCNSL and systemic DLBCL did not differ in their methylation pattern. CONCLUSIONS: Based on the data presented here, PCNSL and DLBCL do not differ in their DNA methylation pattern. Thus, DNA methylation analysis does not support a separation of PCNSL and DLBCL into individual entities. However, PCNSL and DLBCL differ in their DNA methylation pattern from non- malignant controls.


Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Metilación de ADN , Linfoma/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Análisis por Conglomerados , Islas de CpG/genética , Células Madre Embrionarias/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Hematopoyesis/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Proteínas del Grupo Polycomb , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología
10.
JCI Insight ; 4(2)2019 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-30674721

RESUMEN

Tumor radioresistance leading to local therapy failure remains a major obstacle for successful treatment of high-grade glioma. We hypothesized that distinct radiobiological features of particle therapy with carbon ions may circumvent glioma radioresistance. We demonstrate that carbon irradiation (CIR) efficiently eradicates radioresistant patient-derived glioma stem cells (GSCs), leading to growth inhibition and prolonged survival. The impact of CIR at the tumor-stroma interface was further investigated in 2 syngeneic mouse and 2 orthotopic GSC xenograft models. Intriguingly, tumor regressions and long-term local controls were observed at doses greater than or equal to 15-Gy CIR. Fractionated CIR further prolonged survival. The enhanced relative biological effectiveness of CIR in vivo was attributed to its potent antiangiogenic effects and eradication of radioresistant hypoxic tumor cells. Blockade of the HIF1-α/stromal cell-derived factor 1/CXCR4 axis by CIR reduced the recruitment of microglia and myeloid-derived suppressor cells (CD11b+Gr1+). Consequently, CIR abrogated M2-like immune polarization and enhanced the influx of CD8+ cells, generating an immunopermissive niche. We report that radiotherapy with carbon ions could surmount several central glioma resistance mechanisms by eradicating hypoxic and stem cell-like tumor cells, as well as modulating the glioma niche toward an antiangiogenic and less immunosuppressive state. Conclusively, potentially novel rationales for CIR in conquering glioma radioresistance are provided.

11.
J Neuropathol Exp Neurol ; 67(7): 720-7, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18596541

RESUMEN

Primary lymphomas of the CNS (PCNSLs) show molecular features of the late germinal center exit B-cell phenotype and are impaired in their terminal differentiation as indicated by a lack of immunoglobulin class switching. Because the positive regulatory domain I protein with ZNF domain (PRDM1/BLIMP1) is a master regulator of terminal B-cell differentiation into plasma cells, we investigated a series of 21 PCNSLs for the presence of mutations in the PRDM1 gene and alterations in the expression pattern of the PRDM1 protein. Direct sequencing of all coding exons of the PRDM1 gene identified deleterious mutations associated with abrogation of PRDM1 protein expression in 4 of 21 (19%) PCNSLs. Thus, similar to systemic diffuse large B-cell lymphomas, PRDM1 may be a tumor suppressor in some PCNSL and contribute to lymphomagenesis by impairing terminal differentiation.


Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Regulación Neoplásica de la Expresión Génica/genética , Linfoma de Células B/genética , Proteínas Represoras/genética , Eliminación de Secuencia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Recurrencia
12.
Nat Clin Pract Oncol ; 5(6): 337-47, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18431377

RESUMEN

Classical antineoplastic treatments such as chemotherapy or radiation can efficiently eradicate the majority of proliferating and genetically unstable malignant cells within neoplastic lesions. There is increasing evidence, however, that these regimens frequently fail to eliminate a minor subpopulation of resistant tumor cells that have distinct features of somatic stem cells. These serve as a reservoir for disease recurrence, and are the origin of metastatic growth. These so-called cancer stem cells (CSCs) or cancer-initiating cells represent often a rare, highly self-renewing population within the tumor mass, which is thought to be the only one required for both initiation and maintenance of disease. Tumor-cell populations enriched for CSC activity were originally identified in leukemias, but have now also been uncovered in a number of solid cancers. Their marked resistance towards classical antitumor regimens is mediated by the combination of several critical features, including relative dormancy, efficient DNA repair, high expression of multidrug-resistance-type membrane transporters and protection by a hypoxic niche environment. We review the concept of CSCs with particular emphasis on the mechanism of therapy resistance, and discuss potential future therapeutic interventions with the goal of specifically eliminating CSCs in a clinical setting.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Animales , Humanos , Células Madre Neoplásicas/citología
13.
Mol Cancer Res ; 5(12): 1232-40, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18171980

RESUMEN

Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA- or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas.


Asunto(s)
Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Caspasa 3/metabolismo , Glioblastoma/enzimología , Glioblastoma/patología , Caspasa 3/genética , Caspasa 8/genética , Caspasa 8/metabolismo , Inhibidores de Caspasas , Línea Celular Tumoral , Movimiento Celular/fisiología , Inhibidores Enzimáticos/farmacología , Gelsolina/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Invasividad Neoplásica , ARN Interferente Pequeño , Receptor fas/metabolismo
14.
J Neuropathol Exp Neurol ; 66(3): 230-7, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17356384

RESUMEN

Recent studies point to a role of nuclear factor (NF)-kappaB signaling in a subset of diffuse large B cell lymphomas. We have analyzed the expression of 21 genes encoding NF-kappaB family members, upstream modulators, and targets in 32 primary central nervous system lymphomas (PCNSLs) by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with nonmalignant germinal center centroblasts, expression of BCL10, REL, IAP1, and TRAF1 was significantly lower in PCNSLs, whereas that of BAX, BCLXL, BCL2, MALT1, CARD9, CARD10, CARD11, CARD14, CCND2, cFLIP, RELA, RELB, NFKB1, NFKB2, and IRF4 was higher. Hierarchical clustering of gene expression data revealed two distinct subgroups of PCNSLs, which were characterized by significantly different transcriptional levels, predominantly of BCL10, but also of REL and IAP1. Thus, these quantitative RT-PCR data with expression of genes of the NF-kappaB family as well as NF-kappaB-regulated genes together with immunohistochemical detection of nuclear RELA and REL indicate activation of the NF-kappaB pathway in PCNSLs, which may contribute to their high proliferative activity and the low level of apoptosis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias del Sistema Nervioso Central/clasificación , Linfoma/clasificación , FN-kappa B , Transducción de Señal/fisiología , Anciano , Anciano de 80 o más Años , Proteína 10 de la LLC-Linfoma de Células B , Linfocitos B/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Análisis por Conglomerados , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Linfoma/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
15.
Brain Pathol ; 17(2): 146-50, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17388945

RESUMEN

About 15% of sporadic gastrointestinal and endometrial tumors show the microsatellite instability (MSI) phenotype because of loss of DNA mismatch repair (MMR) function. The incidence of MSI in tumors of the central nervous system still remains controversial. Previous studies reported a particular high frequency of MSI (approximately 25%) in young patients suffering from high-grade gliomas. Based on these data and the fact that in different tumor entities MMR deficiency defines a subgroup of tumors with distinct pathogenesis and particular clinicopathological features that may have impact on prognosis and therapy, we screened 624 gliomas from 71 young and 553 adult patients for MMR deficiency by MSI analysis using three highly sensitive diagnostic markers. Alterations of MMR protein expression was examined by immunohistochemistry. A malignant glioma from an adult patient displayed MSI and concomitant loss of nuclear MSH2 and MSH6 protein expression (0.16%; 1/619). No evidence for MSI or loss of MMR protein expression was observed in 71 gliomas from young patients (0%; 0/71) including 41 high-grade astrocytic tumors. Overall, we observed a much lower incidence of MSI among high-grade pediatric gliomas than initially reported and suggest that MMR deficiency does not play a major role in the pathogenesis of glial neoplasms.


Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Inestabilidad de Microsatélites , Adulto , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Niño , Proteínas de Unión al ADN/metabolismo , Glioma/metabolismo , Glioma/patología , Humanos , Inmunohistoquímica , Reacción en Cadena de la Polimerasa
16.
Brain ; 129(Pt 11): 2992-3005, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16844716

RESUMEN

The amyloid beta-protein (Abeta) is the main component of Alzheimer's disease-related senile plaques. Although Abeta is associated with the development of Alzheimer's disease, it has not been shown which forms of Abeta induce neurodegeneration in vivo and which types of neurons are vulnerable. To address these questions, we implanted DiI crystals into the left frontocentral cortex of APP23 transgenic mice overexpressing mutant human APP (amyloid precursor protein gene) and of littermate controls. Traced commissural neurons in layer III of the right frontocentral cortex were quantified in 3-, 5-, 11- and 15-month-old mice. Three different types of commissural neurons were traced. At 3 months of age no differences in the number of labelled commissural neurons were seen in APP23 mice compared with wild-type mice. A selective reduction of the heavily ramified type of neurons was observed in APP23 mice compared with wild-type animals at 5, 11 and 15 months of age, starting when the first Abeta-deposits occurred in the frontocentral cortex at 5 months. The other two types of commissural neurons did not show alterations at 5 and 11 months. At 15 months, the number of traced sparsely ramified pyramidal neurons was reduced in addition to that of the heavily ramified neurons in APP23 mice compared with wild-type mice. At this time Abeta-deposits were seen in the neo- and allocortex as well as in the basal ganglia and the thalamus. In summary, our results show that Abeta induces progressive degeneration of distinct types of commissural neurons. Degeneration of the most vulnerable neurons starts in parallel with the occurrence of the first fibrillar Abeta-deposits in the neocortex, that is, with the detection of aggregated Abeta. The involvement of additional neuronal subpopulations is associated with the expansion of Abeta-deposition into further brain regions. The vulnerability of different types of neurons to Abeta, thereby, is presumably related to the complexity of their dendritic morphology.


Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/fisiología , Células Dendríticas/patología , Neuronas/patología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Axones/patología , Western Blotting , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Ratones , Ratones Transgénicos , Neocórtex/patología , Placa Amiloide/patología , Prosencéfalo/metabolismo
17.
Clin Cancer Res ; 12(10): 3019-27, 2006 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-16707597

RESUMEN

PURPOSE: Medulloblastomas represent the most frequent malignant brain tumors of childhood. They are supposed to originate from cerebellar neural precursor cells. Recently, it has been shown that Sonic Hedgehog-induced formation of medulloblastoma in an animal model is significantly enhanced by activation of the phosphatidylinositol 3'-kinase (PI3K) signaling pathway. EXPERIMENTAL DESIGN: To examine a role for PI3K/AKT signaling in the molecular pathogenesis of human medulloblastoma, we did an immunohistochemical study of the expression of Ser473-phosphorylated (p)-AKT protein in 22 medulloblastoma samples: All samples displayed p-AKT expression. To investigate if an activated PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five human medulloblastoma cell lines with increasing concentrations of the PI3K inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The antiproliferative effect could be antagonized by overexpressing constitutively active AKT. As the activation of PI3K/AKT signaling may be associated with alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to frequent allelic losses in medulloblastoma, we screened PTEN for mutations and mRNA expression. RESULTS: Proliferation of all of the medulloblastoma cell lines was dependent on PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss was detected in 16% of the cases. One medulloblastoma cell line was found to carry a truncating mutation in the PTEN coding sequence. Even more important, PTEN mRNA and protein levels were found to be significantly lower in medulloblastomas compared with normal cerebellar tissue of different developmental stages. Reduction of PTEN expression was found to be associated with PTEN promoter hypermethylation in 50% of the tumor samples. CONCLUSIONS: We conclude that activation of the PI3K/AKT pathway constitutes an important step in the molecular pathogenesis of medulloblastoma and that dysregulation of PTEN may play a significant role in this context.


Asunto(s)
Proliferación Celular , Neoplasias Cerebelosas/metabolismo , Meduloblastoma/metabolismo , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Neoplasias Cerebelosas/genética , Niño , Análisis Mutacional de ADN , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Meduloblastoma/genética , Fosfohidrolasa PTEN/biosíntesis , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Transducción de Señal , Células Tumorales Cultivadas
18.
19.
Neurosurgery ; 81(2): 230-239, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28379547

RESUMEN

BACKGROUND: Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections of malignant glioma at a dose of 20 mg/kg; yet, it is unknown whether lower doses may also provide efficacy. OBJECTIVE: To perform a double-blinded randomized study comparing 3 different doses of 5-ALA. METHODS: Twenty-one patients with suspected malignant glioma were randomly assigned to 0.2, 2, or 20 mg/kg 5-ALA. Investigators were unaware of dose. Intraoperatively, regions of interest were first defined in tumor core, margin, and adjacent white matter under white light. Under violet-blue illumination, the surgeon's impression of fluorescence was recorded per region, followed by spectrometry and biopsy. Plasma was collected after administration and analyzed for 5-ALA and protoporphyrin IX (PPIX) content. RESULTS: The positive predictive value of fluorescence was 100%. Visual and spectrometric fluorescence assessment showed 20 mg/kg to elicit the strongest fluorescence in tumor core and margins, which correlated with cell density. Spectrometric and visual fluorescence correlated significantly. A 10-fold increase in 5-ALA dose (2-20 mg/kg) resulted in a 4-fold increase of fluorescence contrast between marginal tumor and adjacent brain. t max for 5-ALA was 0.94 h for 20 mg/kg (0.2 kg: 0.50 h, 2 mg/kg: 0.61 h). Integrated PPIX plasma levels were 255.8 and 779.9 mcg*h/l (2 vs 20 mg/kg). Peak plasma concentrations were observed at 1.89 ± 0.71 and 7.83 ± 0.68 h (2 vs 20 mg/kg; average ± Standard Error of Mean [SEM]). CONCLUSION: The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence.


Asunto(s)
Ácido Aminolevulínico , Neoplasias Encefálicas , Encéfalo , Glioma , Imagen Óptica/métodos , Cirugía Asistida por Computador/métodos , Ácido Aminolevulínico/administración & dosificación , Ácido Aminolevulínico/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/cirugía , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Glioma/diagnóstico por imagen , Glioma/cirugía , Humanos
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