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1.
Nat Commun ; 11(1): 550, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992716

RESUMO

Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that captures authentic cancer pathobiology. Orthotopic engraftment of the neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) results in formation of high-grade gliomas. Similar to patient-derived GBM, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, intra-tumor heterogeneity, and extrachromosomal DNA amplification. Re-engraftment of these primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. These cancer avatar models provide a platform for comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.


Assuntos
Engenharia Genética , Glioblastoma/genética , Glioblastoma/patologia , Células-Tronco Pluripotentes/patologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma , Glioblastoma/metabolismo , Glioma/genética , Glioma/patologia , Humanos , Camundongos , Camundongos SCID , Mutação , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Neurofibromina 1/genética , PTEN Fosfo-Hidrolase/genética , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética
2.
J Cancer Res Clin Oncol ; 146(1): 117-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31844979

RESUMO

PURPOSE: Glioblastoma multiforme (GBM) is a poorly curable disease due to its profound chemoresistance. Despite recent advances in surgery, radiotherapy and chemotherapy, the efficient treatment of GBMs is still a clinical challenge. Beside others, AT101, the R-(-) enantiomer of gossypol, and demethoxycurcumin (DMC), a curcumin-related demethoxy compound derived from Curcuma longa, were considered as possible alternative drugs for GBM therapy. METHODS: Using different human primary GBM cell cultures in a long-term stimulation in vitro model, the cytotoxic and anti-proliferative effects of single and combined treatment with 5 µM AT101 and 5 µM or 10 µM DMC were investigated. Furthermore, western blots on pAkt and pp44/42 as well as JC-1 staining and real-time RT-PCR were performed to understand the influence of the treatment at the molecular and gene level. RESULTS: Due to enhanced anti-proliferative effects, we showed that combined therapy with both drugs was superior to a single treatment with AT101 or DMC. Here, by determination of the combination index, a synergism of the combined drugs was detectable. Phosphorylation and thereby activation of the kinases p44/42 and Akt, which are involved in proliferation and survival processes, were inhibited, the mitochondrial membrane potential of the GBM cells was altered, and genes involved in dormancy-associated processes were regulated by the combined treatment strategy. CONCLUSION: Combined treatment with different drugs might be an option to efficiently overcome chemoresistance of GBM cells in a long-term treatment strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Diarileptanoides/farmacologia , Glioblastoma/tratamento farmacológico , Gossipol/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Diarileptanoides/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Gossipol/administração & dosagem , Gossipol/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
3.
Gene ; 723: 144126, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589963

RESUMO

Non-coding RNAs are known to participate in cancer initiation, progression, and metastasis by regulating the status of chromatin epigenetics and gene expression. Although these non-coding RNAs do not possess defined protein-coding potential, they are involved in the expression and stability of messenger RNA (mRNA). The length of microRNAs (miRs) ranges between 20 and 22 nt, whereas, long non-coding RNAs (lncRNAs) length ranges between 200 nt to 1 Kb. In the case of circular RNAs (circRNAs), the size varies depending upon the length of the exon from where they were derived. Epigenetic regulations of miR and lncRNA genes will influence the gene expression by modulating histone acetylation and methylation patterns. Especially, lncRNAs will act as a scaffold for various epigenetic proteins, such as EZH2 and LSD1, and influence the chromatin epigenetic state at various genomic loci involved at silencing. Thus investigations on the expression of lncRNAs and designing drugs to modulate the expression of these genes will have a profound impact on future therapeutics against cancers such as Glioblastoma Multiforme (GBM) and also against various other diseases. With the recent advancements in genome-wide transcriptomic studies, scientists are focused on the non-coding RNAs and their regulations on various cellular processes involved in GBM and on other types of cancer as well as trying to understand possible epigenetic modulations that help in generating promising therapeutics for the future generations. In this review, the involvement of epigenetic proteins, enzymes that change chromatin architecture and epigenetic landscape and new roles of lncRNAs that are involved in GBM progression are elaborately discussed.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , MicroRNAs/genética , RNA Longo não Codificante/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Ensaios Clínicos como Assunto , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glioblastoma/genética , Humanos
4.
Int J Cancer ; 146(2): 373-387, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31211412

RESUMO

Loss of 5-hydroxymethylcytosine (5hmC) has been associated with mutations of the ten-eleven translocation (TET) enzymes in several types of cancer. However, tumors with wild-type TET genes can also display low 5hmC levels, suggesting that other mechanisms involved in gene regulation might be implicated in the decline of this epigenetic mark. Here we show that DNA hypermethylation and loss of DNA hydroxymethylation, as well as a marked reduction of activating histone marks in the TET3 gene, impair TET3 expression and lead to a genome-wide reduction in 5hmC levels in glioma samples and cancer cell lines. Epigenetic drugs increased expression of TET3 in glioblastoma cells and ectopic overexpression of TET3 impaired in vitro cell growth and markedly reduced tumor formation in immunodeficient mice models. TET3 overexpression partially restored the genome-wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines, while elevated TET3 mRNA levels were correlated with better prognosis in glioma samples. Our results suggest that epigenetic repression of TET3 might promote glioblastoma tumorigenesis through the genome-wide alteration of 5hmC.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Dioxigenases/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Animais , Biópsia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Metilação de DNA , Regulação para Baixo , Glioblastoma/mortalidade , Glioblastoma/patologia , Código das Histonas/genética , Humanos , Camundongos , Prognóstico , RNA Mensageiro/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(11): 5983-5990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704823

RESUMO

BACKGROUND/AIM: DJ-1, an oncogenic molecule, helps to maintain somatic stem cells by reducing the intracellular level of reactive oxygen species (ROS). This study investigated the role of DJ-1 in glioma stem cells (GSCs). MATERIALS AND METHODS: U87-MG (U87) and U251-MG (U251) glioblastoma cell lines that express wild-type and mutant p53, respectively, were used. These were cultured with DJ-1-targeting siRNA and subjected to a variety of in vitro experiments or intracranial transplantation into nude mice. RESULTS: Knockdown of DJ-1 reduced clonogenicity only in U87 cells, which was rescued by p53 depletion. ROS accumulated in DJ-1-depleted cells, although treatment with N-acetyl cysteine, which quenches ROS, did not affect exhaustion of CSCs among U87 cells by DJ-1 knockdown. In a serial transplantation study, DJ-1 knockdown prolonged the survival of mice in secondary transplantation. CONCLUSION: DJ-1 plays a pivotal role in maintenance of stem cell self-renewal in the U87 cell line.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Autorrenovação Celular , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteína Desglicase DJ-1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteína Desglicase DJ-1/antagonistas & inibidores , Proteína Desglicase DJ-1/genética , RNA Interferente Pequeno/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 39(11): 6073-6086, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704835

RESUMO

BACKGROUND/AIM: Oncolytic adenoviruses are promising therapeutic agents against both the bulk of tumor cells and cancer stem cells. The present study intended to test the oncolytic capability of adenovirus serotype 6 (Ad6), which has a lower seroprevalence and hepatotoxicity relatively to adenovirus 5 (Ad5), against the glioblastoma and its cancer stem cells. MATERIALS AND METHODS: Oncolytic efficacy of Ad6 was compared to widespread Ad5 both in vitro and in vivo, using the U87 and U251 human glioblastoma cell lines and subcutaneously transplanted U87 cells in SCID mice, respectively. RESULTS: Ad6 had a dose-dependent cytotoxicity toward glioblastoma cells in vitro and its intratumoral injections lead to a significant (p<0.05) decrease in volume of U87 xenografts, similarly to Ad5. Based on the innate capability of glioblastoma cancer stem cells to internalize a fluorescent-labeled double-stranded DNA probe, the spatial localization of these cells was estimated and it was shown that the number of cancer stem cells tended to decrease under adenovirus therapy as compared to the control group. CONCLUSION: Ad6 was shown to be a promising agent for treating glioblastomas.


Assuntos
Adenovírus Humanos/genética , Glioblastoma/terapia , Células-Tronco Neoplásicas/metabolismo , Terapia Viral Oncolítica , Replicação Viral , Adenovírus Humanos/classificação , Animais , Apoptose , Proliferação de Células , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/virologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mutat Res ; 816-818: 111679, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31715522

RESUMO

Glioblastoma (GBM) is the most lethal type of primary brain tumor. Currently, even with optimal and multimodal cancer therapies, the survival rate of GBM patients remains poor. One reason for inadequate response of GBM tumors to radiotherapy is radioresistance (RR). Thus, there is a critical need for new insights about GBM treatment to increase the chance of treatment. microRNAs (miRNAs) are important regulatory molecules that can effectively control GBM radiosensitivity (RS) by affecting radiation-related signal transduction pathways such as apoptosis, proliferation, DNA repair and cell cycle regulation. miRNAs provide new clinical perspectives for developing effective GBM treatments. A growing body of literature has demonstrated that GBM RS can be modified by modulating the expression of miRNAs such as miR-7, miR-10b, miR-124, miR-128, miR-320, miR-21, miR-203, and miR-153. This paper highlights the miRNAs and the underlying molecular mechanisms that are involved in the RS of GBM. Besides highlighting the role of miRNAs in different signaling pathways, we explain the mechanisms that affect RS of GBM for modulating radiation response at the clinical level.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroRNAs/genética , Tolerância a Radiação/genética , Transdução de Sinais/genética , Animais , Neoplasias Encefálicas/radioterapia , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/radioterapia , Humanos , Tolerância a Radiação/efeitos da radiação , Transdução de Sinais/efeitos da radiação
8.
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
10.
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
11.
World Neurosurg ; 132: e140-e161, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31505292

RESUMO

BACKGROUND: This study aimed to predict methylation status of the O6 methylguanine-DNA methyltransferase (MGMT) gene promoter status by using magnetic resonance imaging radiomics features, as well as univariate and multivariate analysis. METHODS: Eighty-two patients who had an MGMT methylation status were included in this study. Tumors were manually segmented in the 4 regions of magnetic resonance images, 1) whole tumor, 2) active/enhanced region, 3) necrotic regions, and 4) edema regions. About 7000 radiomics features were extracted for each patient. Feature selection and classifier were used to predict MGMT status through different machine learning algorithms. The area under the curve (AUC) of the receiver operating characteristic curve was used for model evaluations. RESULTS: Regarding univariate analysis, the Inverse Variance feature From Gray Level Co-occurrence Matrix in whole tumor segment with 4.5 mm Sigma of Laplacian of Gaussian filter with AUC of 0.71 (P value = 0.002) was found to be the best predictor. For multivariate analysis, the Decision Tree classifier with Select from Model feature selector and LOG (Laplacian of Gaussian) filter in edema region had the highest performance (AUC, 0.78), followed by Ada-Boost classifier with Select from Model feature selector and LOG filter in edema region (AUC, 0.74). CONCLUSIONS: This study showed that radiomics using machine learning algorithms is a feasible noninvasive approach to predict MGMT methylation status in patients with glioblastoma multiforme cancer.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Edema Encefálico/diagnóstico por imagem , Feminino , Genômica , Humanos , Avaliação de Estado de Karnofsky , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Necrose , Distribuição Normal , Valor Preditivo dos Testes , Estudos Retrospectivos
12.
Nat Biotechnol ; 37(11): 1302-1313, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31548728

RESUMO

Targeting membrane proteins could improve the efficacy of T cell-based immunotherapies. To facilitate the identification of T cell targets, we developed a hybrid genetic screening system where the Sleeping Beauty (SB) transposon and single guide RNA cassette are nested in an adeno-associated virus (AAV). SB-mediated genomic integration of the single guide RNA cassette enables efficient gene editing in primary murine T cells as well as a screen readout. We performed in vivo AAV-SB-CRISPR screens for membrane protein targets in CD8+ T cells in mouse models of glioblastoma (GBM). We validated screen hits by demonstrating that adoptive transfer of CD8+ T cells with Pdia3, Mgat5, Emp1 or Lag3 gene editing enhances the survival of GBM-bearing mice in both syngeneic and T-cell receptor transgenic models. Transcriptome profiling, single cell sequencing, cytokine assays and T cell signaling analysis showed that Pdia3 editing in T cells enhances effector functions. Engineered PDIA3 mutant EGFRvIII chimeric antigen T cells are more potent in antigen-specific killing of human GBM cells.


Assuntos
Linfócitos T CD8-Positivos/transplante , Edição de Genes/métodos , Glioblastoma/terapia , Proteínas de Membrana/genética , Transposases/genética , Animais , Antígenos CD/genética , Linfócitos T CD8-Positivos/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Dependovirus/genética , Feminino , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Imunoterapia Adotiva , Masculino , Camundongos , N-Acetilglucosaminiltransferases/genética , Proteínas de Neoplasias/genética , Isomerases de Dissulfetos de Proteínas/genética , RNA Guia/genética , Receptores de Superfície Celular/genética , Transposases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
PLoS Comput Biol ; 15(9): e1006789, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527881

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor. Molecular heterogeneity is a hallmark of GBM tumors that is a barrier in developing treatment strategies. In this study, we used the nonsynonymous mutations of GBM tumors deposited in The Cancer Genome Atlas (TCGA) and applied a systems level approach based on biophysical characteristics of mutations and their organization in patient-specific subnetworks to reduce inter-patient heterogeneity and to gain potential clinically relevant insights. Approximately 10% of the mutations are located in "patches" which are defined as the set of residues spatially in close proximity that are mutated across multiple patients. Grouping mutations as 3D patches reduces the heterogeneity across patients. There are multiple patches that are relatively small in oncogenes, whereas there are a small number of very large patches in tumor suppressors. Additionally, different patches in the same protein are often located at different domains that can mediate different functions. We stratified the patients into five groups based on their potentially affected pathways that are revealed from the patient-specific subnetworks. These subnetworks were constructed by integrating mutation profiles of the patients with the interactome data. Network-guided clustering showed significant association between the groups and patient survival (P-value = 0.0408). Also, each group carries a set of signature 3D mutation patches that affect predominant pathways. We integrated drug sensitivity data of GBM cell lines with the mutation patches and the patient groups to analyze the possible therapeutic outcome of these patches. We found that Pazopanib might be effective in Group 3 by targeting CSF1R. Additionally, inhibiting ATM that is a mediator of PTEN phosphorylation may be ineffective in Group 2. We believe that from mutations to networks and eventually to clinical and therapeutic data, this study provides a novel perspective in the network-guided precision medicine.


Assuntos
Neoplasias Encefálicas/genética , Análise por Conglomerados , Biologia Computacional/métodos , Glioblastoma/genética , Mutação/genética , Neoplasias Encefálicas/epidemiologia , Mapeamento Cromossômico , Glioblastoma/epidemiologia , Humanos , Modelos Moleculares , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Medicina de Precisão/métodos
14.
Turk Neurosurg ; 29(5): 778-784, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31529454

RESUMO

AIM: To evaluate the frequency and prognostic significance of microsatellite instability (MSI) in patients with glioblastoma (GBM), an immunohistochemical analysis of mismatch repair (MMR) proteins was performed. MATERIAL AND METHODS: A total of 71 patients with GBM who underwent surgery between 2011 and 2019, were included in the study. MMR protein expression was examined using immunohistochemistical analysis of tumor tissue samples; the association between the MMR status and clinicopathological findings was evaluated. RESULTS: Immunohistochemical analysis revealed expressions of MLH1, MSH2, MSH6, and PMS2 proteins in 67 (94.4%), 65 (91.5%), 67 (94.4%), and 64 (90.1%) patients, respectively. Among the 71 patients, 64 (90.1%) expressing all MMR proteins were considered microsatellite stable (MSS), and 7 (9.9%) patients showing loss of at least one of the MMR proteins were considered to show MSI. Tumor recurrence was noted in 25 (39.1%) patients in the MSS GBM group, and 4 (57.1%) patients in the MSI GBM group (p=0.433). The overall median survival was 30.65 ± 5.1 and 10.71 ± 5.2 months in the MSS GBM and MSI GBM groups, respectively (p=0.059). CONCLUSION: The results of this study showed no significant relationships between MMR protein expression and recurrence rates or overall survival in patients with GBM.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Instabilidade de Microssatélites , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Reparo de Erro de Pareamento de DNA/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
15.
Nat Commun ; 10(1): 4013, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488827

RESUMO

Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Glioblastoma/metabolismo , Histonas/metabolismo , Proteínas de Membrana/metabolismo , Metaloproteínas/metabolismo , Ubiquitinação/fisiologia , Animais , Neoplasias Encefálicas , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/terapia , Células HEK293 , Humanos , Camundongos , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fosforilação , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , alfa Carioferinas/metabolismo
16.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502574

RESUMO

The antitumor effect of calycosin has been widely studied, but the targets of calycosin against glioblastomas are still unclear. In this study we focused on revealing c-Met as a potential target of calycosin suppressing glioblastomas. In this study, suppressed-cell proliferation and cell invasion together with induced-cell apoptosis appeared in calycosin-treated U251 and U87 cells. Under treatment of calycosin, the mRNA expression levels of Dtk, c-Met, Lyn and PYK2 were observed in U87 cells. Meanwhile a western blot assay showed that c-Met together with matrix metalloproteinases-9 (MMP9) and phosphorylation of the serine/threonine kinase AKT (p-AKT) was significantly down-regulated by calycosin. Furthermore, overexpressed c-Met in U87 enhanced the expression level of MMP9 and p-AKT and also improved cell invasion. Additionally, the expression levels of c-Met, MMP9 and p-AKT were inhibited by calycosin in c-Met overexpressed cells. However, an AKT inhibitor (LY294002) only effected on MMP9 and p-AKT, not on c-Met. These data collectively indicated that calycosin possibility targeting on c-Met and exert an anti-tumor role via MMP9 and AKT.


Assuntos
Glioblastoma/tratamento farmacológico , Isoflavonas/farmacologia , Metaloproteinase 9 da Matriz/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
17.
Cancer Discov ; 9(9): 1161-1163, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481405

RESUMO

In this issue of Cancer Discovery, Gimple and colleagues examine superenhancers in glioblastoma and glioma stem cells (GSC), identifying one which promotes expression of ELOVL2, an enzyme in polyunsaturated fatty acid (PUFA) synthesis. They find that ELOVL2 products help maintain cell membrane organization and EGFR signaling in GSCs, and that targeting PUFA metabolism along with EGFR offers a potential novel therapeutic strategy for glioblastoma.See related article by Gimple et al., p. 1248.


Assuntos
Glioblastoma/genética , Glioma , Epigênese Genética , Receptores ErbB , Humanos , Células-Tronco Neoplásicas
18.
PLoS Comput Biol ; 15(8): e1007090, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31386654

RESUMO

As malignant transformation requires synchronization of growth-driving signaling (S) and metabolic (M) pathways, defining cancer-specific S-M interconnected networks (SMINs) could lead to better understanding of oncogenic processes. In a systems-biology approach, we developed a mathematical model for SMINs in mutated EGF receptor (EGFRvIII) compared to wild-type EGF receptor (EGFRwt) expressing glioblastoma multiforme (GBM). Starting with experimentally validated human protein-protein interactome data for S-M pathways, and incorporating proteomic data for EGFRvIII and EGFRwt GBM cells and patient transcriptomic data, we designed a dynamic model for EGFR-driven GBM-specific information flow. Key nodes and paths identified by in silico perturbation were validated experimentally when inhibition of signaling pathway proteins altered expression of metabolic proteins as predicted by the model. This demonstrated capacity of the model to identify unknown connections between signaling and metabolic pathways, explain the robustness of oncogenic SMINs, predict drug escape, and assist identification of drug targets and the development of combination therapies.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/genética , Carcinogênese , Linhagem Celular Tumoral , Biologia Computacional , Simulação por Computador , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/etiologia , Glioblastoma/genética , Humanos , Redes e Vias Metabólicas , Modelos Biológicos , Mutação , Mapas de Interação de Proteínas , Transdução de Sinais , Biologia de Sistemas
19.
Nat Commun ; 10(1): 3601, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399589

RESUMO

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching.


Assuntos
Predisposição Genética para Doença/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Imidazóis/farmacologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Camundongos , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Clin Neurosci ; 68: 1-8, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31416731

RESUMO

Molecular aberrations of malignancy are becoming widely recognized as important predictive and prognostic markers for treatment response and survival in oncology and have been linked to the discovery of novel treatment targets. This area of research in glioblastoma continues to evolve. The aim of this scoping review was to document the hallmark molecular characteristics of long-term survivors of glioblastoma. MEDLINE, Scopus and EMBASE were searched with core concepts: (1) glioblastoma, (2) long-term survivor and (3) molecular OR mutation. A thematic analysis was undertaken of the 18 included studies. Four main classes of characteristics were obtained: IDH mutation, MGMT methylation, other known characteristics and novel discoveries. While MGMT methylation or the combination with IDH mutation are suggested to be hallmark characteristics, there remains enough uncertainty to suggest further factors may be involved, such as CD34 expression. Further research is required to accurately describe hallmark molecular characteristics of long-term survivors to assist in defining these patients at diagnosis, preventing treatment complications and discovering novel treatments.


Assuntos
Neoplasias Encefálicas/genética , Sobreviventes de Câncer , Glioblastoma/genética , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/mortalidade , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Supressoras de Tumor/genética
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