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1.
Indian J Cancer ; 56(3): 197-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389380

RESUMO

BACKGROUND: Wilms' tumor 1 (WT1) mutation has recently been detected in gliomas. Growing data indicate that WT1 mutation plays a causal role in gliomagenesis and is overexpressed in most glioblastomas. An emerging immunotherapy targeting WT1 has shown to be effective in resistant glioblastomas in clinical trials. WT1 expression and its potential utility in various grades of astrocytomas is still unclear and needs further elucidation. The evaluation of WT1 can be done by molecular or immunohistochemical methods. As immunohistochemistry is easier with wider routine use, immunoexpression of this biomarker was studied. AIM: The aim of this study was to characterize WT1 immunoexpression across different histological grades of astrocytomas to routinely aid in diagnosis and reproducibility and to assess the association between WT1 and immunomarker isocitrate dehydrogenase (IDH1). MATERIAL AND METHODS: This was an observational prospective study on 79 cases of astrocytomas. RESULTS: Seventy-nine astrocytomas including 11 recurrent tumors were assessed for WT1 by immunohistochemistry. WT1 expression was detected in all astrocytomas (100%). The control group of reactive gliosis was negative. WT1 score correlated with histological tumor grades (P < 0.001) with higher score in higher grade. It was also observed that different tumor grades depicted two distinct expression patterns. WT1 score and pattern were valuable in differentiating high- and low-grade astrocytomas. CONCLUSION: This study supports the oncogenic role of WT1 in astrocytomas. WT1 was found to be valuable in distinguishing different grades of astrocytomas. WT1 can aid in differentiating neoplastic process from reactive gliosis, particularly in recurrent tumors. Higher expression in glioblastomas supports its immunotherapy potential.


Assuntos
Astrocitoma/classificação , Astrocitoma/patologia , Biomarcadores Tumorais/metabolismo , Imuno-Histoquímica/métodos , Recidiva Local de Neoplasia/patologia , Proteínas WT1/metabolismo , Astrocitoma/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Estudos Prospectivos
2.
Mol Med Rep ; 20(3): 2227-2235, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322210

RESUMO

Elevated plasma homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is an independent risk factor for neurodegenerative diseases. Hcy, even at a low concentration, can promote free radical formation and increase oxidative stress, leading to neuronal death, which may be an important mechanism underlying the pathogenesis of neurodegenerative diseases. Although several reports have indicated that the nuclear translocation of glyceraldehyde 3­phosphate dehydrogenase (GAPDH) may be involved in Hcy­induced apoptosis, the exact mechanism remains to be fully elucidated. The siah E3 ubiquitin protein ligase 1 (siah­1) gene was found to be critical for the translocation of GAPDH from the cytoplasm to the nucleus. In the present study, the role of siah­1 was investigated in the nuclear translocation of GAPDH in rat C6 astroglioma cells treated with Hcy. C6 cells were treated with various concentrations of Hcy for 48 h and the expression level of siah­1 was examined using reverse transcription­quantitative polymerase chain reaction and western blotting analysis. In addition, the subcellular localization of siah­1 and GAPDH and the interaction between these two factors were investigated by immunofluorescence staining and co­immunoprecipitation assay, respectively. The results showed that Hcy at a high concentration increased the expression of siah­1 and induced nuclear translocation of siah­1 and GAPDH. In addition, siah­1 knockdown by siah­1 small interfering RNA significantly decreased the Hcy­induced nuclear accumulation of GAPDH and inhibited the impairment of C6 cells. These findings suggest that siah­1 is involved in Hcy­induced cell damage by promoting the nuclear translocation of GAPDH.


Assuntos
Astrocitoma/metabolismo , Núcleo Celular/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Homocisteína/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Astrocitoma/patologia , Linhagem Celular Tumoral , Ratos
3.
J Neurooncol ; 144(1): 137-146, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214915

RESUMO

INTRODUCTION: Epithelioid glioblastoma (EGBM) and anaplastic pleomorphic xanthoastrocytoma (APXA) are two rare entities with different prognoses. However, they share certain morphological and molecular features. MATERIALS AND METHODS: To better recognize EGBM and APXA and identify the prognostic factors associated with these tumors, EZH2 status, BRAF V600E mutations, and CDKN2A/B deletions were assessed in 15 APXA and 13 EGBM cases. RESULTS: The expression level of EZH2 was found to increase with tumor grade. Overexpression of EZH2 occurred in 69.2% (9/13) of EGBM cases and 20% (3/15) of APXA cases. In addition, 72.7% (8/11) of EGBM and 12.5% (1/8) of APXA cases harbored a CDKN2A homozygous deletion based on fluorescence in situ hybridization. BRAF V600E mutations were detected in 80% (8/10) of EGBM cases and 42.9% (3/7) of APXA cases. Furthermore, EGBM, which exhibited co-existing low-grade glioma-like lesions, was found to have strong EZH2 expression and high Ki-67 indexes only in epithelioid cells and not in low grade lesions. Univariate analysis demonstrated that abundant epithelioid cells, extensive necrosis, EZH2 overexpression and BRAF V600E mutations were significantly associated with decreased overall survival in EGBM and APXA patients (P < 0.05). CONCLUSIONS: The results suggested that testing for EZH2 expression and BRAF V600E mutations might be helpful to evaluate the prognoses of EGBM and APXA patients. The presence of heterogeneous EZH2 expression in biphasic EGBMs could also contribute to malignant progression.


Assuntos
Astrocitoma/patologia , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Deleção de Genes , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Astrocitoma/classificação , Astrocitoma/genética , Astrocitoma/metabolismo , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Células Epitelioides/metabolismo , Células Epitelioides/patologia , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
4.
BMC Cancer ; 19(1): 473, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109310

RESUMO

BACKGROUND: There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells. METHODS: The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models. RESULTS: The IC50 of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 µM, respectively. A low dose of PB221 (1 µM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 µM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model. CONCLUSIONS: This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide.


Assuntos
Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Proteínas de Membrana/genética , Piperidinas/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Proteínas de Membrana/agonistas , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Tetra-Hidronaftalenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Brain Tumor Pathol ; 36(2): 52-55, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30945015

RESUMO

Pilomyxoid astrocytoma is a variant of pilocytic astrocytoma and the clinical, histological and molecular data point to a very close relationship as well as a more aggressive biological behavior for the former. WHO 2016 classification does not provide a specific grade for these neoplasms, but there is sufficient evidence in the literature that pilomyxoid astrocytoma has slightly worse prognosis than typical pilocytic astrocytoma. There is increasing evidence that in addition to the MAPK pathway alterations, pilomyxoid astrocytomas harbor genetic alterations that distinguish them from typical pilocytic astrocytoma.


Assuntos
Astrocitoma/metabolismo , Astrocitoma/patologia , Astrocitoma/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/fisiologia
6.
J Neurooncol ; 143(2): 187-196, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004262

RESUMO

INTRODUCTION: Tumour-associated angiogenesis is associated with the malignancy and poor prognosis of glioma. Isocitrate dehydrogenase (IDH) mutations are present in the majority of lower-grade (WHO grade II and III) and secondary glioblastomas, but their roles in tumour angiogenesis remain unclear. METHODS: Using magnetic resonance imaging (MRI), the cerebral blood flow (CBF) of IDH-mutated glioma was measured and compared with the IDH-wildtype glioma. The densities of microvessels in IDH-mutated and wildtype astrocytoma and glioblastoma were assessed by immunohistochemical (IHC) staining with CD34, and the pericytes were labelled with α-smooth muscle antigen (α-SMA), neural-glial antigen 2 (NG2) and PDGF receptor-ß (PDGFR-ß), respectively. Furthermore, glia-specific mutant IDH1 knock-in mice were generated to evaluate the roles of mutant IDH1 on brain vascular architectures. The transcriptions of the angiogenesis-related genes were assessed in TCGA datasets, including ANGPT1, PDGFB and VEGFA. The expressions of these genes were further determined by western blot in U87-MG cells expressing a mutant IDH1 or treated with 2-HG. RESULTS: The MRI results indicated that CBF was reduced in the IDH-mutated gliomas. The IHC staining showed that the pericyte coverages of microvessels were significantly decreased, but the microvessel densities (MVDs) were only slightly decreased in IDH-mutated glioma. The mutant IDH1 knock-in also impeded the pericyte coverage of brain microvessels in mice. Moreover, the TCGA database showed the mRNA levels of angiogenesis factors, including ANGPT1, PDGFB and VEGFA, were downregulated, and their promoters were also highly hyper-methylated in IDH-mutated gliomas. In addition, both mutant IDH1 and D-2-HG could downregulate the expression of these genes in U87-MG cells. CONCLUSIONS: Our results suggested that IDH mutations could reduce the pericyte coverage of microvessels in astrocytic tumours by inhibiting the expression of angiogenesis factors. As vascular pericytes play an essential role in maintaining functional blood vessels to support tumour growth, our findings imply a potential avenue of therapeutic strategy for IDH-mutated gliomas.


Assuntos
Astrocitoma/patologia , Isocitrato Desidrogenase/genética , Microvasos/patologia , Mutação , Neovascularização Patológica , Pericitos/patologia , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Circulação Cerebrovascular , Humanos , Isocitrato Desidrogenase/fisiologia , Camundongos , Microvasos/metabolismo , Pericitos/metabolismo , Células Tumorais Cultivadas
7.
Brain Tumor Pathol ; 36(3): 103-111, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30972500

RESUMO

We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3-46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Adolescente , Adulto , Astrocitoma/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/patologia , Humanos , Masculino , Mutação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Telomerase/genética , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo
8.
Cell Biol Int ; 43(6): 706-714, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977573

RESUMO

Early exposure to lead (Pb) has been associated with an elevated risk of developing neurodegenerative diseases. There is evidence that neuronal damage in chronic Pb exposure can be caused by the convergence of glial damage. Apoptosis may be a possible mechanism of Pb-induced cell death in the central nervous system. We tested cellular damage and apoptosis in the spinal cord of Wistar rats treated with Pb. Twelve rats were divided into two groups (n = 6): the control group was treated with only drinking water and the other group received 500 ppm of Pb acetate. After 3 months of Pb treatment, all animals were euthanized and spinal cords were extracted. Morphology was evaluated by Nissl and Kluver-Barrera stainings. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Specific antibodies were used to evaluate Pb damage in oligodendrocytes, astrocytes, and microglia. A large number of apoptotic bodies was observed in the white matter of the Pb-treated group. The Pb-treated group also showed a reduced number of neurons and oligodendrocytes but had an increased number of astrocytes compared with the nontreated group. Our results demonstrate that chronic Pb treatment induces neurodegeneration, demyelination, and astrogliosis in the rat spinal cord.


Assuntos
Intoxicação por Chumbo/metabolismo , Chumbo/efeitos adversos , Medula Espinal/efeitos dos fármacos , Animais , Apoptose/fisiologia , Astrocitoma/metabolismo , Astrocitoma/fisiopatologia , Morte Celular/fisiologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
9.
Cancer Biother Radiopharm ; 34(6): 413-416, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30844298

RESUMO

The aim was to evaluate long-term effectiveness, functional outcome, and side effects of targeted α radiotherapy as an alternative treatment for low-grade gliomas (LGGs) in eloquent brain areas. Five patients with gliomas World Health Organization (WHO) II-IV were treated with tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-213Bi substance P. In this study, the LGG patients' (WHO II) clinical and radiological long-term outcome was examined. Ten years after treatment with DOTA-213Bi substance P, both LGG patients are still alive without evidence for tumor recurrence and without new functional deficits. Targeted α radiotherapy of LGG might have the potential of long-term tumor control, due to the short tissue range of α particles especially for eloquently located LGG.


Assuntos
Astrocitoma/radioterapia , Neoplasias Encefálicas/radioterapia , Recidiva Local de Neoplasia/prevenção & controle , Compostos Organometálicos/uso terapêutico , Substância P/análogos & derivados , Adulto , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Humanos , Prognóstico , Substância P/uso terapêutico
10.
Nat Commun ; 10(1): 1023, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833574

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Astrocitoma/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Genoma Humano/genética , Glioma/metabolismo , Histonas/metabolismo , Receptores de Ativinas Tipo I/genética , Animais , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Histonas/genética , Humanos , Camundongos , Mutação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
11.
Life Sci Alliance ; 2(2)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30910807

RESUMO

Neural stem/progenitor cells (NSPCs) of the ventricular-subventricular zone (V-SVZ) are candidate cells of origin for many brain tumors. However, whether NSPCs in different locations within the V-SVZ differ in susceptibility to tumorigenic mutations is unknown. Here, single-cell measurements of signal transduction intermediates in the mechanistic target of rapamycin complex 1 (mTORC1) pathway reveal that ventral NSPCs have higher levels of signaling than dorsal NSPCs. These features are linked with differences in mTORC1-driven disease severity: introduction of a pathognomonic Tsc2 mutation only results in formation of tumor-like masses from the ventral V-SVZ. We propose a direct link between location-dependent intrinsic growth properties imbued by mTORC1 and predisposition to tumor development.


Assuntos
Astrocitoma/metabolismo , Astrocitoma/patologia , Carcinogênese/metabolismo , Ventrículos Laterais/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Células-Tronco Neurais/metabolismo , Esclerose Tuberosa/patologia , Adolescente , Animais , Células Cultivadas , Criança , Pré-Escolar , Suscetibilidade a Doenças/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fator Nuclear 1 de Tireoide/metabolismo
12.
Asian Pac J Cancer Prev ; 20(2): 479-485, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30803210

RESUMO

Background: Leptin, an adipocytokine functions via the leptin receptor, OB-Rb that contains an intact intracellular domain and activates the JAK/STAT signalling cascade. It stimulates growth, migration and invasion of cancer cells in vitro potentiating angiogenesis. Recently, the involvement of leptin in tumor progression is being explored. Gliomas exhibit poor prognosis, low survival rates demanding for novel therapeutic regimens resulting in discovery of many potential biomarkers and pharmaceutical targets. We analysed the potential role of leptin and OB-Rb in carcinogenesis of malignant gliomas. Methods: Sixty fresh tissue samples of diffuse gliomas were collected after tumor excision. Real time PCR, immunohistochemical (IHC) analysis and western blot analysis were carried out to assess the expression of leptin and its receptor. Results: The present study demonstrates the expression of leptin and LepR and their involvement in tumor progression. Of the 60 cases, 57 cases (95%) and 53 cases (88.3%) showed amplification for leptin and OB-Rb respectively. The expression of these proteins were measured semi-quantitatively and correlated with degree of malignancy (p<0.05). The bands were visualised on western blot. Conclusion: Leptin may be valued as a pharmaceutical target and anti-leptin compounds could be developed as drugs in mono- or combined therapies for these tumors.


Assuntos
Astrocitoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Carcinogênese/metabolismo , Leptina/metabolismo , Oligodendroglioma/metabolismo , Receptores para Leptina/metabolismo , Adulto , Idoso , Astrocitoma/genética , Astrocitoma/patologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/patologia , Feminino , Seguimentos , Humanos , Leptina/genética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Oligodendroglioma/genética , Oligodendroglioma/patologia , Estudos Prospectivos , Receptores para Leptina/genética
13.
Glia ; 67(8): 1417-1433, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30667110

RESUMO

Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.


Assuntos
Astrocitoma/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Animais , Astrocitoma/classificação , Astrocitoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Isoformas de Proteínas/metabolismo
14.
Exp Neurol ; 311: 135-147, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30243796

RESUMO

Spinal cord astrocytomas (SCAs) have discernibly unique signatures in regards to epidemiology, clinical oncological features, genetic markers, pathophysiology, and research and therapeutic challenges. Overall, there are presently very limited clinical management options for high grade SCAs despite progresses made in validating key molecular markers and standardizing tumor classification. The endeavors were aimed to improve diagnosis, therapy design and prognosis assessment, as well as to define more effective oncolytic targets. Efficacious treatment for high grade SCAs still remains an unmet medical demand. This review is therefore focused on research state updates that have been made upon analyzing clinical characteristics, diagnostic classification, genetic and molecular features, tumor initiation cell biology, and current management options for SCAs. Particular emphasis was given to basic and translational research endeavors targeting SCAs, including establishment of experimental models, exploration of unique profiles of SCA stem cell-like tumor survival cells, characterization of special requirements for effective therapeutic delivery into the spinal cord, and development of donor stem cell-based gene-directed enzyme prodrug therapy. We concluded that precise understanding of molecular oncology, tumor survival mechanisms (e.g., drug resistance, metastasis, and cancer stem cells/tumor survival cells), and principles of Recovery Neurobiology can help to create clinically meaningful experimental models of SCAs. Establishment of such systems will expedite the discovery of efficacious therapies that not only kill tumor cells but simultaneously preserve and improve residual neural function.


Assuntos
Astrocitoma/terapia , Terapia Genética/tendências , Procedimentos Neurocirúrgicos/tendências , Recuperação de Função Fisiológica/fisiologia , Neoplasias da Medula Espinal/terapia , Transplante de Células-Tronco/tendências , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Terapia Genética/métodos , Humanos , Neurobiologia , Procedimentos Neurocirúrgicos/métodos , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/metabolismo , Transplante de Células-Tronco/métodos , Resultado do Tratamento
15.
Brain Pathol ; 29(2): 193-204, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30222900

RESUMO

Granular cell astrocytoma (GCA) is a rare adult infiltrating glioma subtype. We studied a series of 39 GCAs. Median age of presentation was 57.8 years and most cases developed in the frontal or temporal lobes. Tumors included grade II (n = 14), grade III (n = 11), and grade IV (n = 14) by WHO criteria. Granular cell morphology was diffuse in 31 (79%) cases and partial in eight (21%). Immunohistochemistry showed frequent positivity for GFAP (28 of 31), OLIG2 (16 of 16), and CD68 (27 of 30), but HAM56, CD163, and IBA-1 histiocytic markers were all negative (22 of 22). IDH1(R132H) was negative in all the cases tested (16 of 16), while ATRX expression was retained (12 of 12). Cytogenetics demonstrated monosomy 10 (6 of 6) cases, +7 in 4 (of 6), -13q in 4 of 6, and -14 in 4 of 6. Next-generation sequencing demonstrated mutations in PTEN/PIK3 genes in 6/13 (46%), NF1 in 3 of 10 (30%), TP53 in 3 of 13 (23%), PALB2 in 3 of 10 (30%), STAG2 in 3 of 10 (30%), EGFR mutation/amplification in 3 of 13 (23%), and AR in 2 of 10 (20%). CDKN2A/B deletion was identified in 5 of 13 (30%) cases (homozygous deletion in 4). The TERT C228T mutation was identified in 9 of 13 (69%). No mutations were encountered in IDH1, IDH2, CIC, FUBP1, H3F3A, BRAF or ATRX genes. The mean overall survival was 11.3 months. Patients >60 years old at diagnosis had a worse survival than patients <60 years (P = 0.001). There were no statistically significant differences in survival by WHO grade, extent of granular cell change, sex or MIB-1 (P > 0.05). GCA is a variant of IDH-wildtype diffuse glioma with aggressive behavior irrespective of grade and extent of granular cell morphology, and with molecular genetic features corresponding to primary glioblastoma.


Assuntos
Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/patologia , Tumor de Células Granulares/genética , Tumor de Células Granulares/metabolismo , Tumor de Células Granulares/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Regiões Promotoras Genéticas/genética
16.
Hum Pathol ; 86: 38-48, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30496796

RESUMO

Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor occurring mostly in children and young adults. Next-generation sequencing of 295 cancer-related genes was used to investigate the molecular profiles of 13 cases of PXA. We found that BRAF V600E (5/13; 38%), FANCA/D2/I/M (5/13; 38%), PRKDC (4/13; 31%), NF1 (3/13; 23%), and NOTCH2/3/4 (3/13; 23%) alterations were the most frequent somatic gene mutations. However, neither PTEN nor EGFR mutation, which is frequently present in glioblastoma, was detected. The KRAS mutation in PXA is reported for the first time in these tumors. Microsatellite stability was present in all cases. Because mutations of FANCA and BRAF and copy number variations of CDKN2A/B are more frequent in PXA than in glioblastoma, they might be used to distinguish the 2 tumors. The MAPK pathway is involved in the pathogenesis of PXA and may be an effective target for treatment.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Mutação , Adolescente , Adulto , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
17.
J Neurooncol ; 141(2): 373-382, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30570705

RESUMO

PURPOSES: Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs. METHODS: In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data. RESULTS: Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway. CONCLUSIONS: In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.


Assuntos
Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Substância Branca/metabolismo , Adolescente , Astrocitoma/genética , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Neurofibromatose 1/genética
18.
Int J Neurosci ; 129(2): 171-178, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30146921

RESUMO

OBJECTIVES: Astrocytoma represents most noted malignancy of the brain. The overall survival rate of patients with progressive form remains dismal despite of the present clinical advancements. Search for biomarkers can open new avenues of therapeutic measures to curb the progressive astrocytic tumors. Nck1 is reported to be involved in actin cytoskeleton rearrangement and neuronal migration. Here, we have determined prognostic importance of Nck1 protein in astrocytoma progression. Temporal lobe epilepsy tissues were used as control. METHODS: Real time PCR was used to analyze Nck1 transcript expression while western blotting and immunohistochemistry techniques were used to study expression on translational levels. Protein expression in western blots was categorized as Nck1 positive and Nck1 negative. We further seen the prognostic significance of Nck1 in 246 glioblastoma tissue samples as visible from the TCGA database. RESULTS: We find Nck1 RNA and protein was upregulated significantly in high grade tissues as compared to low grade and control tissue samples (p < 0.05). Logrank test and Kaplan-Meier analysis signified the use of Nck1 as independent prognostic marker for astrocytoma progression and its expression levels were correlated with poor survival in surgically resected human tissue samples (Chi square = 10.7, p = 0.001). Further, glioblastoma was noticed to be predominant at frontal and temporal lobe. CONCLUSION: On account of it's over expression, Nck1 appears as possible biomarker for astrocytoma progression and may serve as an important therapeutic target. Prominent origin of glioblastoma at frontal and temporal lobe suggests possible involvement of tissue specific developmental or transcriptional factors in origin of tumors.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Proteínas Oncogênicas/metabolismo , Adulto , Astrocitoma/diagnóstico , Biomarcadores Tumorais/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Rev Assoc Med Bras (1992) ; 64(12): 1129-1133, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30569990

RESUMO

OBJECTIVE: This study aims to compare estrogen receptor expression between low and high-grade astrocytomas. METHOD: A study using paraffin blocks of glial tumors from the Anatomy Pathology archives of São Marcos Hospital was carried out and began after approval by the Review Board of the Federal University of Piaui. Specimens were histochemically marked with an anti-ER alpha antibody. Brown-stained nuclei were considered positive, regardless of reaction intensity. Data were statistically analyzed using the Mann-Whitney test and Spearman's correlation. Statistical significance was established at p<0.05. RESULTS: The mean percentage of nuclei stained with anti-ER alpha in low-and high-grade astrocytomas was 0.04 and zero, respectively, while Spearman's correlation showed a strong negative association between low and high-grade tumors (p<0.001) and (r= -0.67), respectively. CONCLUSION: In the current study, estrogen receptor expression was positive only in low-grade astrocytomas and nil in high-grade astrocytomas, showing that ER expression declines with the grade of tumor malignancy.


Assuntos
Astrocitoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores Estrogênicos/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Humanos , Imuno-Histoquímica , Gradação de Tumores
20.
Neurol India ; 66(6): 1726-1731, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504574

RESUMO

Background: The plethora of biomarkers available for the diagnosis and prognostication of gliomas has refined the classification of gliomas. The new World Health Organization (WHO) 2016 classification integrates the phenotypic and genotyping features for a more robust diagnosis. Materials and Methods: Fifty gliomas with oligodendroglial morphology according to the WHO 2007 classification were analyzed for isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations by polymerase chain reaction, 1p/19q status by fluorescent in situ hybridization (FISH), and IDH1 and X-linked alpha-thalassemia retardation (ATRX) expression by immunohistochemistry. Tumors were reclassified into oligodendrogliomas, astrocytomas, and glioblastomas (GBMs) according to the new "integrated" diagnostic approach. Results: 30% of previously diagnosed oligodendrogliomas and almost 90% of oligoastrocytomas were reclassified as astrocytomas. Twenty gliomas showed 1p/19q co-deletion, while 18 gliomas showed polysomy of chromosome 1/19. Polysomy of chromosome 1/19 was significantly associated with astrocytic tumors (P ≤ 0.001). Loss of ATRX expression was seen in 20 of 23 WHO grade II/III astrocytomas and 3 of 7 GBMs. All WHO grade II and III gliomas in our cohort showed IDH1/2 mutations. Moreover, 4 of 7 GBMs showed the wild-type IDH1/2 mutation, and 2 of 3 GBMs which showed IDH1/2 mutations were secondary GBMs. There was no significant difference in progression-free and overall survival between WHO grade II and III gliomas, possibly because all these tumors showed IDH1/2 mutations. In multivariate analysis, only the WHO grade (grade IV versus II and III combined) was significantly associated with increased risk of recurrence and death (P = 0.016 and 0.02). Conclusion: The new integrated diagnosis provides a more meaningful classification, removing the considerable subjectivity that existed previously.


Assuntos
Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Glioma/diagnóstico , Oligodendroglia/metabolismo , Oligodendroglioma/diagnóstico , Adolescente , Adulto , Astrocitoma/metabolismo , Astrocitoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Oligodendroglia/patologia , Oligodendroglioma/metabolismo , Oligodendroglioma/patologia , Prognóstico , Proteína Nuclear Ligada ao X/metabolismo , Adulto Jovem
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