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1.
Life Sci ; 236: 116917, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614149

RESUMO

AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in glioma patients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS: NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of glioma patients, especially in GBM patients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , NF-kappa B/metabolismo , Fatores de Transcrição NFI/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Nus , NF-kappa B/genética , Fatores de Transcrição NFI/genética , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Treat Rev ; 80: 101896, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541850

RESUMO

Glioblastomas are intrinsic brain tumors thought to originate from neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors. Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy define the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of disease. Specifically, targeting cellular pathways frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tryrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Reposicionamento de Medicamentos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Terapia de Alvo Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
J Biol Regul Homeost Agents ; 33(5): 1451-1463, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507151

RESUMO

Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/citologia , Neovascularização Patológica , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Encéfalo , Criança , Pré-Escolar , Células Endoteliais , Citometria de Fluxo , Imunofluorescência , Humanos , Lactente , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Cancer Sci ; 110(11): 3486-3496, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483918

RESUMO

Bone morphogenetic protein (BMP) signaling plays important roles in glioblastoma multiforme (GBM), a lethal form of brain tumor. BMP reduces GBM tumorigenicity through its differentiation- and apoptosis-inducing effects on glioma-initiating cells (GIC). However, some GIC do not respond to the tumor suppressive effects of BMP. Using a phosphoreceptor tyrosine kinase array, we found that EPHA6 (erythropoietin-producing hepatocellular carcinoma receptor A6) phosphorylation was regulated by BMP-2 signaling in some GIC. Analysis of The Cancer Genome Atlas showed that EPHA6 expression was lower in patients with GBM than in the normal brain, and that high EPHA6 expression was correlated with better prognosis. EPHA6 receptor increased the susceptibility of both sensitive and resistant GIC to BMP-2-induced apoptosis. The cooperative effect on apoptosis induction depended on the kinase activity of BMP type I receptor but was independent of EPHA6 kinase function. Overexpression of the EPHA6 receptor in GIC resulted in the formation of a protein complex of EPHA6 receptor and the BMP type I receptor ALK-2, which was associated with BMP-induced apoptosis in GIC. Intracranial injection of GIC into nude mice showed that gain-of-function of EPHA6 together with BMP-2 pretreatment slowed GBM tumor progression in the mouse brain and promoted mouse survival. In summary, EPHA6 together with BMP-2 signaling led to apoptotic cell death in GIC, and thus is a putative tumor suppressor in GBM.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Apoptose , Proteína Morfogenética Óssea 2/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptor EphA6/metabolismo , Animais , Proteína Morfogenética Óssea 2/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Prognóstico , Proteínas Supressoras de Tumor/metabolismo
5.
BMC Bioinformatics ; 20(1): 463, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500569

RESUMO

BACKGROUND: The Human Protein Atlas (HPA) aims to map human proteins via multiple technologies including imaging, proteomics and transcriptomics. Access of the HPA data is mainly via web-based interface allowing views of individual proteins, which may not be optimal for data analysis of a gene set, or automatic retrieval of original images. RESULTS: HPAanalyze is an R package for retrieving and performing exploratory analysis of data from HPA. HPAanalyze provides functionality for importing data tables and xml files from HPA, exporting and visualizing data, as well as downloading all staining images of interest. The package is free, open source, and available via Bioconductor and GitHub. We provide examples of the use of HPAanalyze to investigate proteins altered in the deadly brain tumor glioblastoma. For example, we confirm Epidermal Growth Factor Receptor elevation and Phosphatase and Tensin Homolog loss and suggest the importance of the GTP Cyclohydrolase I/Tetrahydrobiopterin pathway. Additionally, we provide an interactive website for non-programmers to explore and visualize data without the use of R. CONCLUSIONS: HPAanalyze integrates into the R workflow with the tidyverse framework, and it can be used in combination with Bioconductor packages for easy analysis of HPA data.


Assuntos
Análise de Dados , Armazenamento e Recuperação da Informação , Proteínas de Neoplasias/metabolismo , Software , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Humanos
6.
Curr Top Med Chem ; 19(17): 1521-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31362676

RESUMO

Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.


Assuntos
Neoplasias Encefálicas/metabolismo , Espectrometria de Massas , Neoplasias Encefálicas/patologia , Humanos
7.
Molecules ; 24(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288488

RESUMO

In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Radioisótopos de Gálio/química , Glioblastoma/diagnóstico por imagem , Oligopeptídeos/química , Compostos Radiofarmacêuticos/química , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Feminino , Radioisótopos de Flúor , Glioblastoma/metabolismo , Humanos , Camundongos SCID , Transplante de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Tomografia Computadorizada por Raios X
8.
Cell Prolif ; 52(5): e12665, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332862

RESUMO

OBJECTIVES: Abnormal activation of NF-κB signalling is a major mechanism of apoptosis resistance in glioblastoma multiforme (GBM). Therefore, better understanding of the regulation of NF-κB signalling has a significant impact for GBM therapy. Here, we uncovered a critical role of the small GTPase RND3 in regulating the p65 subunit of NF-κB and NF-κB signalling in GBM. MATERIALS AND METHODS: Human GBM samples, GBM cells and a human orthotopic GBM-xenografted animal model were used. The mechanisms of RND3 in regulation of NF-κB signalling and GBM cell apoptosis were examined by luciferase assay, quantitative PCR, immunostaining, immunoblotting, immunofluorescence, coimmunoprecipitation, TUNEL staining, JC-1 analysis and flow cytometry. RESULTS: Overexpression of RND3 led to reduced p65 activity in GBM-cultured cells and a GBM animal model, indicating that the NF-κB pathway is negatively regulated by RND3 in GBM. Mechanistically, we found that RND3 bound p65 and promoted p65 ubiquitination, leading to decreased p65 protein levels. Furthermore, RND3 enhanced cleaved caspase 3 levels and promoted apoptosis in GBM cells, and RND3 expression was positively correlated with cleaved caspase 3 and IL-8 in human GBM samples. The effect of RND3 on promoting apoptosis disappeared when p65 ubiquitination was blocked by protease inhibitor carfilzomib or upon co-expression of ectopic p65. CONCLUSIONS: RND3 binds p65 protein and promotes its ubiquitination, resulting in reduced p65 protein expression and inhibition of NF-κB signalling to induce GBM cell apoptosis.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Interleucina-8/metabolismo , Camundongos , Camundongos Nus , Oligopeptídeos/farmacologia , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Transplante Heterólogo , Ubiquitinação/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/genética
9.
J Clin Pathol ; 72(10): 677-681, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31270134

RESUMO

AIMS: Tumour recurrence is inevitable in glioblastoma (GBM) and mostly noted in the peritumoural brain zone (PT). In our previous microarray-based study, we identified Myosin Light Chain 9 (MYL9) as a highly expressed gene in the PT of GBM. Therefore, we aimed to study the expression pattern and clinical significance of MYL9 in GBM. METHODS: Patient samples included three retrospective cohorts: 25 GBM cases with differential biopsies of tumour core and PT, 62 retrospective cases of newly diagnosed GBM with survival information and 20 paired samples (newly diagnosed and recurrent GBM). All tumour tissues, archived as formalin fixed paraffin embedded blocks were retrieved and immunohistochemistry for MYL9 and IDH1 R132H was performed. MYL9 expression was correlated with patient prognosis in our cohort and in The Cancer Genome Atlas (TCGA) and Rembrandt cohorts. It was further evaluated in the 20 paired samples of GBM. RESULTS: MYL9 showed a cytoplasmic membranous staining of tumour cells. The staining pattern was variable and patchy within tumours. Higher MYL9 expression was associated with poor overall and progression-free survival in our and in TCGA and Rembrandt cohorts. The expression of MYL9 was higher in IDH1 R132H immunonegative cases. CONCLUSIONS: We show MYL9 as a novel biomarker, variably expressed in GBM. The association of high MYL9 expression with poor prognosis in newly diagnosed GBM patients and increased expression in recurrent GBM is indicative of its role in conferring tumour aggressiveness.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Cadeias Leves de Miosina/metabolismo , Adulto , Idoso , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Estudos de Coortes , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
10.
Life Sci ; 232: 116657, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306660

RESUMO

AIMS: Constant development of chemotherapeutic strategies has considerably improved the efficiency of tumor treatment. However, adverse effects of chemotherapeutics enforce premature treatment cessation, which leads to the tumor recurrence and accelerated death of oncologic patients. Recently, sodium ascorbate (ASC) has been suggested as a promising drug for the adjunctive chemotherapy of glioblastoma multiforme (GBM) and prostate cancer (PC). To estimate whether ASC can interfere with tumor recurrence between the first and second-line chemotherapy, we analyzed the effect of high ASC doses on the expansion of cells in vitro and in vivo. MAIN METHODS: Brightfield microscopy-assisted approaches were used to estimate the effect of ASC (1-14 mM) on the morphology and invasiveness of human GBM, rat PC and normal mouse 3T3 cells, whereas cytostatic/pro-apoptotic activity of ASC was estimated with flow cytometry. These assays were complemented by the in vitro CellROX-assisted analyses of intracellular oxidative stress and in vivo estimation of GBM tumor invasion. KEY FINDINGS: ASC considerably decreased the proliferation and motility of GBM and PC cells. This effect was accompanied by intracellular ROS over-production and necrotic death of tumor cells, apparently resulting from their "autoschizis". In vivo studies demonstrated the retardation of GBM tumor growth and invasion in the rats undergone intravenous ASC administration, in the absence of detectable systemic adverse effects of ASC. SIGNIFICANCE: Our data support previous notions on anti-tumor activity of high ASC doses. However, autoschizis-related cell responses to ASC indicate that its application in human adjunctive tumor therapy should be considered with caution.


Assuntos
Ácido Ascórbico/administração & dosagem , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Glioblastoma/patologia , Animais , Ácido Ascórbico/farmacologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Invasividade Neoplásica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
11.
Arkh Patol ; 81(3): 27-36, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31317928

RESUMO

OBJECTIVE: To comprehensively assess the functional molecular biological status of different tumor cell populations in glioblastoma samples. MATERIAL AND METHODS: The activity of Ki-67, Bcl-2, and BCL6 expression was determined in 20 tumor samples from patients with glioblastoma. After that, a spatial analysis of heterogeneity in the expression of these markers in different tumor cell populations was carried out using computer and software tools and calculating the percentage of cells (PC) expressing this marker (Ki-67 labeling index (LI)) and a modified histoscore in different cell clusters. RESULTS: Analysis of heterogeneity in the distribution of Ki-67, Bcl-2, and BCL6 expression could identify five cell clusters differing in the expression level of the above-mentioned markers. The most active cluster was the perivascular one (the highest mean Ki-67 LI (22.23±1.4%) and histoscore (118.59±3.36%); BCL6 PC and histoscore (17.4±1.4 and 79.32±4.86%, respectively). The least proliferative activity was observed in the perinecrotic cluster (Ki-67 LI (6.83±0.5%) and histoscore (62.46±2.25%)), while the neighboring transient necrotic cluster displayed sufficiently active proliferative processes (Ki-67 LI (18.39±0.56%) and histoscore (112.65±2.76%)). In addition, the transient vascular cluster was noted for a low proliferative activity (Ki-67 LI (8.37±0.35%) and histoscore (75.48±2.04%)). Finally, the intermediate cluster was characterized by the mean values of all parameters (Ki-67 LI (10.68±0.39%) and histoscore (95.73±2.37%). It should be noted that the differences in the expression activity for markers in these clusters were statistically significant. CONCLUSION: The perivascular cluster carries the greatest potential for tumor progression and recurrence, which agrees with the data available in the literature: the perivascular zone is the most important niche for glioma stem cells that make a considerable contribution to the malignant potential of glioblastoma. Tumor pathogenesis and morphogenesis are a complex interweaving of interrelated factors, the realization of which within the framework of a multi-level heterochronic pathological process leads to the segregation of tumor cells and to the appearance of separate cell populations described in this paper.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-bcl-6 , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Antígeno Ki-67 , Índice Mitótico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
13.
Artigo em Russo | MEDLINE | ID: mdl-31166314

RESUMO

OBJECTIVE: To study the effect of metabolic characteristics of the tumor determined by 99mTc-MIBI single-photon emission computed tomography (SPECT) and various molecular genetic features on the outcomes of combination treatment of hemispheric glioblastomas. MATERIAL AND METHODS: This single-center prospective cohort study involved 68 patients aged 25-78 years (38 males and 30 females) with primary glioblastomas. Hypermetylation of the promotor region of the MGMT gene was observed in 24 (42%) out of 57 patients. The IDH1 mutation was revealed in two (3.5%) patients. The catamnestic data were available for 66 out of 68 patients. The first SPECT/CT study was carried out before chemoradiation therapy; the second SPECT/CT study was performed after the chemoradiation therapy. In each study, quantitative measures were calculated for the early (15-30 min after the patient had received a radiopharmaceutical) and late (after 45-60 min) phases. RESULTS: The actuarial survival rates after 12 and 24 months were 69.6 and 29.1%, respectively. The median overall survival rate was 17.5 months (95% CI 12.9-20.3). Favorable prognostic factors for overall survival included the higher uptake index (UI) in the late phase compared to UI in the early phase of the first SPECT/CT study (p=0.0444), dynamics of changes in UI during the second SPECT/CT compared to baseline over 10% (p=0.0436), MGMT hypermethylation (p=0.0003), and duration of the period between surgery and initiation of chemoradiotherapy being <1 month (p=0.0008). No statistically significant correlations were revealed between the absolute UI values in the tumor and its molecular genetic features. CONCLUSION: The 99mTc-MIBI SPECT/CT can be used to predict overall survival and to plan radiation therapy of glioblastoma as it is more readily available at primary healthcare facilities than amino acid PET.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Tecnécio Tc 99m Sestamibi , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
14.
Cancer Sci ; 110(8): 2558-2572, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215106

RESUMO

Glioma, the most common human primary brain tumor, is characterized by invasive capabilities and angiogenesis. Vasorin (VASN), a transmembrane protein, is reported to be associated with vascular injury repair and is overexpressed in some human tumors. However, its role in tumor progression and angiogenesis in glioma is unknown. In this study, VASN was shown to be overexpressed in high-grade gliomas, and the expression level correlated with tumor grade and microvessel density in glioma specimens. Glioma patients with high VASN expression had a shorter overall survival time. Knockdown of VASN in glioma cells by shRNA significantly inhibited the malignancy of glioma, including cell proliferation, colony formation, invasion, and sphere formation. Ectopic expression of VASN increased glioma progression in vitro. The expression of VASN correlated with the mesenchymal type of glioblastoma multiforme (GBM) subtyped by gene set enrichment analysis (GSEA). Our results showed that the concentration of VASN was increased in the conditioned medium (CM) from glioma cells with VASN overexpression, and the CM from glioma cells with knockdown or overexpressed VASN inhibited or promoted HUVEC migration and tubulogenesis in vitro, respectively. Glioma growth and angiogenesis were stimulated upon ectopic expression of VASN in vivo. The STAT3 and NOTCH pathways were found to be activated and inhibited by VASN overexpression. Our findings suggest that VASN stimulates tumor progression and angiogenesis in glioma, and, as such, represents a novel therapeutic target for glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteínas de Transporte/metabolismo , Glioma/metabolismo , Glioma/patologia , Proteínas de Membrana/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Adulto , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Nat Commun ; 10(1): 2541, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186414

RESUMO

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFß, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.


Assuntos
Astrócitos/metabolismo , Citocinas/metabolismo , Glioblastoma/imunologia , Microglia/metabolismo , Astrócitos/citologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação , Janus Quinases/metabolismo , Microglia/citologia , Fenótipo , Fatores de Transcrição STAT/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Técnicas de Cultura de Tecidos
16.
DNA Cell Biol ; 38(7): 688-699, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188028

RESUMO

This study was aimed to identify hub genes associated with the development of glioblastoma (GBM) by conducting a bioinformatic analysis. The raw gene expression data were downloaded from the Gene Expression Omnibus database and The Cancer Genome Atlas project. After the differentially expressed genes (DEGs) were identified, the functional enrichment analysis of DEGs was conducted. Subsequently, the protein-protein interaction (PPI) network, molecular complex detection clusters, and transcriptional factor (TF)-miRNA-target regulatory network were constructed, respectively. Furthermore, the survival analysis of prognostic outcomes and genes was analyzed. In addition, the expression of key genes was validated by quantitative real-time PCR (qRT-PCR) analysis. A total of 884 DEGs, including 418 upregulated and downregulated genes, were identified between GBM and normal samples. The PPI network comprised a set of 3418 pairs involving 751 nodes, and AKT1 and CDK2 were the critical genes in the network. A total of seven clusters were identified, the genes in which were intensively associated with cell cycle, cholinergic synapse, and extracellular matrix (ECM)-receptor interaction. qRT-PCR analysis indicated that AKT1 and CDK2 were significantly upregulated, and NRXN3 and NPTX2 were significantly downregulated in GBM samples. The TF-miRNA-target regulatory networks were built, in which CCNB1, RFC5, microRNA524, and microRNA34b were key regulators. There were 43 genes, including NPTX2 and NRXN3, significantly related to the prognostic outcomes of GBM patients. These crucial genes might be promising options for GBM treatment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , MicroRNAs/genética , Transcriptoma , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Células Cultivadas , Ciclina B1/genética , Ciclina B1/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Replicação C/genética , Proteína de Replicação C/metabolismo
17.
BMC Cancer ; 19(1): 441, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088402

RESUMO

BACKGROUND: Glioblastoma is a disease with high heterogeneity that has long been difficult for doctors to identify and treat. ARHI is a remarkable tumor suppressor gene in human ovarian cancer and many other cancers. We found over-expression of ARHI can also inhibit cancer cell proliferation, decrease tumorigenicity, and induce autophagic cell death in human glioma and inhibition of the late stage of autophagy can further enhance the antitumor effect of ARHI through inducing apoptosis in vitro or vivo. METHODS: Using MTT assay to detect cell viability. The colony formation assay was used to measure single cell clonogenicity. Autophagy associated morphological changes were tested by transmission electron microscopy. Flow cytometry and TUNEL staining were used to measure the apoptosis rate. Autophagy inhibitor chloroquine (CQ) was used to study the effects of inhibition at late stage of autophagy on ARHI-induced autophagy and apoptosis. Protein expression were detected by Western blot, immunofluorescence and immunohistochemical analyses. LN229-derived xenografts were established to observe the effect of ARHI in vivo. RESULTS: ARHI induced autophagic death in glioma cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activites of ARHI. In our research, we observed the inhibition of RAS-AKT-mTOR signaling in ARHI-glioma cells and blockade of autophagy flux at late stage by CQ enhanced the cytotoxicity of ARHI, caused accumulation of autophagic vacuoles and robust apoptosis. As a result, the inhibition of RAS augmented autophagy of glioma cells. CONCLUSION: ARHI may also be a functional tumor suppressor in glioma. And chloroquine (CQ) used as an auxiliary medicine in glioma chemotherapy can enhance the antitumor effect of ARHI, and this study provides a novel mechanistic basis and strategy for glioma therapy.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas ras/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Autofagia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas ras/genética , Proteínas rho de Ligação ao GTP/genética
18.
Mol Cells ; 42(4): 321-332, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31085806

RESUMO

The brain is the most common metastatic site of lung adenocarcinoma; however, the mechanism of this selective metastasis remains unclear. We aimed to verify the hypothesis that exposure of tumor cells to the brain microenvironment leads to changes in their gene expression, which promotes their oriented transfer to the brain. A549 and H1299 lung adenocarcinoma cells were exposed to human astrocyte-conditioned medium to simulate the brain microenvironment. Microarray analysis was used to identify differentially expressed genes, which were confirmed by quantitative real-time PCR and western blotting. Knockdown experiments using microRNAs and the overexpression of genes by cell transfection were performed in addition to migration and invasion assays. In vitro findings were confirmed in clinical specimens using immunohistochemistry. We found and confirmed a significant increase in insulin-like growth factor binding protein-3 (IGFBP3) levels. Our results also showed that the up-regulation of IGFBP3 promoted A549 cell epithelial-mesenchymal transition, migration, and invasion, while the knockdown of IGFBP3 resulted in decreased cell motility. We also found that Transforming growth factor-ß (TGF-ß)/Mothers against decapentaplegic homolog 4 (Smad4)-induced epithelial-mesenchymal transition was likely IGFBP3-dependent in A549 cells. Finally, expression of IGFBP3 was significantly elevated in pulmonary cancer tissues and intracranial metastatic tissues. Our data indicate that up-regulation of IGFBP3 might mediate brain metastasis in lung adenocarcinoma, which makes it a potential therapeutic target.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Astrócitos/citologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , Regulação para Cima , Células A549 , Adenocarcinoma de Pulmão/genética , Astrócitos/metabolismo , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
19.
Int J Mol Sci ; 20(10)2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091655

RESUMO

An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a wide range in overall survival, from months for the worst cases of glioblastoma (GBM) to years for lower grade astrocytic and oligodendroglial tumors. We previously identified a change in the cell adhesion molecule PTPmu in brain tumors that results in the generation of proteolytic fragments. We developed agents to detect this cell surface-associated biomarker of the tumor microenvironment. In the current study, we evaluated the PTPmu biomarker in tissue microarrays and individual tumor samples of adolescent and young adult (n = 25) and adult (n = 69) glioma populations using a fluorescent histochemical reagent, SBK4-TR, that recognizes the PTPmu biomarker. We correlated staining with clinical data and found that high levels of the PTPmu biomarker correlate with increased survival of glioma patients, including those with GBM. Patients with high PTPmu live for 48 months on average, whereas PTPmu low patients live only 22 months. PTPmu high staining indicates a doubling of patient survival. Use of the agent to detect the PTPmu biomarker would allow differentiation of glioma patients with distinct survival outcomes and would complement current molecular approaches used in glioma prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Masculino , Prognóstico , Microambiente Tumoral
20.
Int J Mol Sci ; 20(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035417

RESUMO

Glioblastoma multiforme and medulloblastoma are the most frequent high-grade brain tumors in adults and children, respectively. Standard therapies for these cancers are mainly based on surgical resection, radiotherapy, and chemotherapy. However, intrinsic or acquired resistance to treatment occurs almost invariably in the first case, and side effects are unacceptable in the second. Therefore, the development of new, effective drugs is a very important unmet medical need. A critical requirement for developing such agents is to identify druggable targets required for the proliferation or survival of tumor cells, but not of other cell types. Under this perspective, genes mutated in congenital microcephaly represent interesting candidates. Congenital microcephaly comprises a heterogeneous group of disorders in which brain volume is reduced, in the absence or presence of variable syndromic features. Genetic studies have clarified that most microcephaly genes encode ubiquitous proteins involved in mitosis and in maintenance of genomic stability, but the effects of their inactivation are particularly strong in neural progenitors. It is therefore conceivable that the inhibition of the function of these genes may specifically affect the proliferation and survival of brain tumor cells. Microcephaly genes encode for a few kinases, including CITK, PLK4, AKT3, DYRK1A, and TRIO. In this review, we summarize the evidence indicating that the inhibition of these molecules could exert beneficial effects on different aspects of brain cancer treatment.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Microcefalia/metabolismo , Microcefalia/patologia , Animais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Proteínas Serina-Treonina Quinases/metabolismo
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