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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 924-929, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33148388

RESUMO

Objective To investigate the expression of cathepsin S (CTSS) in temozolomide-resistant glioblastoma T98G (T98G-R) cells. Methods The differentially expressed genes involved in T98G-R cells were obtained from NCBI database, and the expression of CTSS in glioblastoma was analyzed in Gene Expression Profiling Interactive Analysis (GEPIA2) and Chinese Glioma Genome Atlas (CGGA) database. Real-time quantitative PCR and Western blot analysis were used to detect CTSS expression in T98G cells and T98G-R cells. The correlation between CTSS expression level and patient prognosis was analyzed using the Cancer Genome Atlas (TCGA) database. Results Gene CTSS was screened out by comparing the differentially expressed genes in T98G-R cells using NCBI GEO chip data GSE2221. GEPIA2 database analysis showed higher CTSS expression in glioblastoma tissues than in normal tissues. Both mRNA and protein levels of CTSS in T98G-R cells were significantly higher than those in T98G cells. TCGA database showed that GBM patients with high CTSS expression exhibited poorer prognosis. Conclusion CTSS is highly expressed in T98G-R cells and is associated with poor prognosis in patients.


Assuntos
Neoplasias Encefálicas/genética , Catepsinas/genética , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/genética , Temozolomida/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Humanos , Prognóstico
2.
Nat Commun ; 11(1): 5424, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110073

RESUMO

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.


Assuntos
Ferroptose , Glioblastoma/fisiopatologia , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral , Coenzima A Ligases/genética , Coenzima A Ligases/imunologia , Progressão da Doença , Feminino , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Ferro/imunologia , Camundongos , Camundongos Nus , Necrose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/imunologia
3.
Anticancer Res ; 40(11): 6229-6236, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109560

RESUMO

BACKGROUND/AIM: To compare the GeneXpert® O6-methylguanine DNA methyltransferase (MGMT) methylation prototype (GX MGMT) assay with pyrosequencing in glioblastomas. MATERIALS AND METHODS: The MGMT methylation status was retrospectively assessed in formalin-fixed paraffin embedded (FFPE) tumor blocks from 262 glioblastoma patients obtained from three independent cohorts using either a standard of care pyrosequencing laboratory developed test or the GX MGMT assay. RESULTS: The concordance rate was 92.1% (58/63) for Oregon Health and Science University (OSHU) samples, 91.7% (88/96) for Medical University of Vienna (MUV) samples, and 82.5% (85/103) for Kepler University Hospital (KUH) samples. Patients with MGMT promoter hypermethylation assessed by pyrosequencing or the GX MGMT test had a significantly longer overall survival compared to patients without hypermethylation (HR=0.43, 95%CI=0.26-0.72, p=0.001 and HR=0.51, 95%CI=0.31-0.84, p=0.008, respectively). CONCLUSION: Standardized, simplified, and on-demand testing of MGMT promoter methylation by the GX MGMT assay is feasible.


Assuntos
Bioensaio/métodos , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
4.
Life Sci ; 261: 118486, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32976881

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common subtype of brain cancer, encompassing 16% of all primary brain cancers. The prognosis of GBM is poor, with a 5-year-survial of approximately 5%. Increasing evidence has revealed that chemokines in the tumor microenvironment (TME) are often altered, thus affecting tumor proliferation and metastasis. METHOD: Multi-omics and bioinformatics tools were utilized to clarify the role of CXC chemokine in GBM. RESULT: Most CXC chemokines were found to be differentially regulated in GBM, which correlated with patient prognosis. CXC chemokines were found to activate cancer-related signaling pathways, thus affecting immune infiltration. Interestingly, this was found to be associated with drug resistance. Most CXC chemokines were significantly correlated with abundance of B cells, CD8+ cells and dendritic cells. Furthermore, somatic copy number alterations of CXC chemokines can inhibit dendritic cell infiltration. Moreover, CXCL1 was selected as a hub gene, and several kinase, miRNA and transcription factor targets of CXCL1 were identified. CONCLUSION: our study provides novel insights into CXC chemokine expression and their role in the GBM microenvironment. These results are able to provide more data about prognostic biomarkers and therapeutic targets of GBM.


Assuntos
Neoplasias Encefálicas/genética , Quimiocinas CXC/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Neoplasias Encefálicas/diagnóstico , Redes Reguladoras de Genes , Glioblastoma/diagnóstico , Humanos , Prognóstico , Microambiente Tumoral
5.
BMC Bioinformatics ; 21(Suppl 13): 383, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32938364

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors and its average survival time is less than 1 year after diagnosis. RESULTS: Firstly, this study aims to develop the novel survival analysis algorithms to explore the key genes and proteins related to GBM. Then, we explore the significant correlation between AEBP1 upregulation and increased EGFR expression in primary glioma, and employ a glioma cell line LN229 to identify relevant proteins and molecular pathways through protein network analysis. Finally, we identify that AEBP1 exerts its tumor-promoting effects by mainly activating mTOR pathway in Glioma. CONCLUSIONS: We summarize the whole process of the experiment and discuss how to expand our experiment in the future.


Assuntos
Algoritmos , Neoplasias Encefálicas/genética , Biologia Computacional/métodos , Glioblastoma/genética , Glioma/genética , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Glioma/mortalidade , Humanos , Análise de Sobrevida
6.
Nat Commun ; 11(1): 4660, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938908

RESUMO

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Histona Desacetilase 1/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Camundongos SCID , Fenilbutiratos/farmacologia , Transdução de Sinais , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Commun ; 11(1): 4709, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948765

RESUMO

Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.


Assuntos
Reparo do DNA , Instabilidade Genômica , Glioblastoma/genética , Células-Tronco Neoplásicas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Apoptose , Proteína BRCA1 , Neoplasias Encefálicas/genética , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Glioblastoma/patologia , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/genética , Tolerância a Radiação , Radiação Ionizante , Transcriptoma
8.
PLoS One ; 15(9): e0239551, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946518

RESUMO

Pathway analysis is an informative method for comparing and contrasting drug-induced gene expression in cellular systems. Here, we define the effects of the marine natural product fucoxanthin, separately and in combination with the prototypic phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002, on gene expression in a well-established human glioblastoma cell system, U87MG. Under conditions which inhibit cell proliferation, LY-294002 and fucoxanthin modulate many pathways in common, including the retinoblastoma, DNA damage, DNA replication and cell cycle pathways. In sharp contrast, we see profound differences in the expression of genes characteristic of pathways such as apoptosis and lipid metabolism, contributing to the development of a differentiated and distinctive drug-induced gene expression signature for each compound. Furthermore, in combination, fucoxanthin synergizes with LY-294002 in inhibiting the growth of U87MG cells, suggesting complementarity in their molecular modes of action and pointing to further treatment combinations. The synergy we observe between the dietary nutraceutical fucoxanthin and the synthetic chemical LY-294002 in producing growth arrest in glioblastoma, illustrates the potential of nutri-pharmaceutical combinations in targeting this challenging disease.


Assuntos
Cromonas/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Morfolinas/administração & dosagem , Xantofilas/administração & dosagem , Apoptose/efeitos dos fármacos , Produtos Biológicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Suplementos Nutricionais , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glioblastoma/dietoterapia , Humanos , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem
9.
Nat Commun ; 11(1): 3811, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732914

RESUMO

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.


Assuntos
Neoplasias Encefálicas/radioterapia , Reparo do DNA/genética , Glioblastoma/radioterapia , Guanosina Monofosfato/metabolismo , Tolerância a Radiação/genética , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Feminino , Glioblastoma/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Nucleosídeos de Purina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncogene ; 39(38): 6043-6052, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32801336

RESUMO

Although rare, glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment, and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness, and resistance, as they carry oncogenic material. Moreover, EVs have been shown to communicate locally in a paracrine way but also at remote throughout the organism. Indeed, recent reports demonstrated the presence of brain tumor-derived EVs into body fluids such as plasma and cerebrospinal fluid. Fluid-associated EVs have indeed been suspected to reflect quantitative and qualitative information about the status and fate of the tumor and can potentially act as a resource for noninvasive biomarkers that might assist in diagnosis, treatment, and follow-up of glioblastoma patients. Here, we coined the name vesiclemia to define the concentration of plasmatic EVs, an intuitive term to be directly transposed in the clinical jargon.


Assuntos
Neoplasias Encefálicas/metabolismo , Vesículas Extracelulares/metabolismo , Glioblastoma/metabolismo , Animais , Transporte Biológico , Biomarcadores Tumorais , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Comunicação Celular , Fracionamento Celular/métodos , Gerenciamento Clínico , Progressão da Doença , Glioblastoma/sangue , Glioblastoma/diagnóstico , Glioblastoma/genética , Humanos , Técnicas de Diagnóstico Molecular , Microambiente Tumoral/genética
11.
Oncogene ; 39(36): 5902-5915, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32737433

RESUMO

PI3K/Akt/mTOR signaling pathway activity is highly elevated in glioblastoma (GBM). Although rapamycin is known to inhibit this pathway, GBM patients are resistant to rapamycin monotherapy. This may be related to mutations of tumor suppressor phosphatase and tensin homolog (PTEN). Here, we show that higher expression of E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) in GBM is correlated with poor prognosis. Smurf1 promotes cell growth and colony formation by accelerating cell cycle and aberrant signaling pathways. In addition, we show that Smurf1 ubiquitylates and degrades PTEN. We further demonstrate that the oncogenic role of Smurf1 is dependent on PTEN. Upregulated Smurf1 impairs PTEN activity, leading to consistent activation of PI3K/Akt/mTOR signaling pathway; and depletion of Smurf1 dramatically inhibits cell proliferation and tumor growth. Moreover, loss of Smurf1 abolishes the aberrant regulation of PTEN, causing negative feedback on PI3K/Akt/mTOR signaling pathway, and thus leading to rescue of tumor sensitivity to rapamycin in an orthotopic GBM model. Taken together, we show that Smurf1 promotes tumor progression via PTEN, and combined treatment of Smurf1 knockdown with mammalian target of rapamycin (mTOR) inhibition reduces tumor progression. These results identify a unique role of Smurf1 in mTOR inhibitor resistance and provide a strong rationale for combined therapy targeting GBM.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Oncogenes , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Deleção de Genes , Perfilação da Expressão Gênica , Genes Reporter , Glioblastoma/mortalidade , Glioblastoma/patologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Mutação , Prognóstico , Sirolimo/farmacologia , Mutações Sintéticas Letais , Ubiquitinação
12.
Ecotoxicol Environ Saf ; 202: 110940, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800223

RESUMO

Recent evidence indicates that chronic, low-dose exposure to mixtures of pesticides can cause adverse responses in a variety of cells, tissues and organs, although interactions between pesticides circulating in the blood and cancer cells remain largely unexplored. The aim of this study was to investigate the potential of a mixture of four pesticides to induce multidrug resistance against the chemotherapeutic agents cisplatin, 5-fluorouracil and temozolomide in the human U87 glioblastoma cell line, and to explore the molecular mechanisms underlying this resistance. We found that the repeated administration of the pesticide mixture (containing the insecticides chlorpyrifos-ethyl and deltamethrin, the fungicide metiram, and the herbicide glyphosate) induced a strong drug resistance in U87 cells. The resistance was durable and transferred to subsequent cell generations. In addition, we detected a significant over-expression of the ATP-binding cassette (ABC) membrane transporters P-gp/ABCB1 and BRCP/ABCG2 as well as a glutathione-S-transferase (GST)/M1-type cellular detoxification function, known to have important roles in multidrug resistance, thus providing molecular support for the acquired multidrug resistance phenotype and shedding light on the mechanism of resistance. We further determined that there was lower mortality in the resistant brain tumor cells and that the mitochondrial apoptosis pathway was activated at a lower rate after chemotherapy compared to non-resistant control cells. In addition, multidrug-resistant cells were found to have both higher motility and wound-healing properties, suggesting a greater metastatic potential. Our results suggest that the investigation of P-gp, BRCP and GST/M1 multidrug resistance gene expression and/or protein levels in biopsy specimens of brain tumor patients who were at risk of pesticide exposure could be beneficial in determining chemotherapy dose and prolonging patient survival.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Praguicidas/toxicidade , Testes de Toxicidade Crônica , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/farmacologia
13.
J Cancer Res Clin Oncol ; 146(11): 2885-2896, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32779022

RESUMO

PURPOSE: Glioblastoma is the most aggressive form of brain tumors. A better understanding of the molecular mechanisms leading to its evolution is essential for the development of treatments more effective than the available modalities. Here, we aim to identify molecular drivers of glioblastoma development and recurrence by analyzing DNA CpG methylation patterns in sequential samples. METHODS: DNA was isolated from 22 pairs of primary and recurrent formalin-fixed, paraffin-embedded glioblastoma specimens, and subjected to reduced representation bisulfite sequencing. Bioinformatic analyses were conducted to identify differentially methylated sites and pathways, and biostatistics was used to test correlations among clinical and pathological parameters. RESULTS: Differentially methylated pathways likely involved in primary tumor development included those of neuronal differentiation, myelination, metabolic processes, synapse organization and endothelial cell proliferation, while pathways differentially active during glioblastoma recurrence involved those associated with cell processes and differentiation, immune response, Wnt regulation and catecholamine secretion and transport. CONCLUSION: DNA CpG methylation analyses in sequential clinical specimens revealed hypomethylation in certain pathways such as neuronal tissue development and angiogenesis likely involved in early tumor development and growth, while suggested altered regulation in catecholamine secretion and transport, Wnt expression and immune response contributing to glioblastoma recurrence. These pathways merit further investigations and may represent novel therapeutic targets.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA/genética , Glioblastoma/genética , Glioblastoma/patologia , Adulto , Idoso , Ilhas de CpG/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Brain Tumor Pathol ; 37(4): 154-158, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32749624

RESUMO

Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.


Assuntos
Neoplasias Encefálicas/genética , Análise Mutacional de DNA/métodos , Glioblastoma/genética , Mutação , Recidiva Local de Neoplasia/genética , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas/genética , Telomerase/genética , Humanos , Isocitrato Desidrogenase/genética , Sensibilidade e Especificidade
15.
Brain Tumor Pathol ; 37(4): 136-144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761533

RESUMO

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1-MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1-MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72-17.05), p = 0.004). Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.


Assuntos
Neoplasias Encefálicas/genética , Fusão Gênica/genética , Estudos de Associação Genética , Glioblastoma/genética , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proteínas do Citoesqueleto/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Taxa de Sobrevida
16.
Pol J Pathol ; 71(2): 127-137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32729303

RESUMO

Numerous genetic pathways associated with glioblastoma development have been identified. In this study, we investigated the prognostic significance of IDH1 and ATRX mutations and WT-1 and p53 expression in glioblastomas and that of surgical methods, radiotherapy and chemotherapy. 83 patients with glioblastomas were retrospectively evaluated. Immunohistochemical analysis was performed for IDH1, ATRX and WT-1 expression. Tumour cells were positive for IDH1 in 9.6% of the patients. In 4.8% of the patients, loss of ATRX expression was observed in tumour cells; 86.7% of the patients were WT-1 positive, and 12.05% of the patients were p53 positive. No statistically significant difference was found in the progression-free and overall survival according to IDH1, ATRX, WT-1 and p53 expression. There was a statistically significant difference in the progression-free and overall survival according to the radiotherapy status. There was a statistically significant difference in the overall survival according to the chemotherapy status. There was no statistically significant difference in the progression-free and overall survival according to the surgical method. IDH1 and ATRX mutations, p53 overexpression and WT-1 expression alone did not have a significant effect on the prognosis of patients with glioblastoma; however, radiotherapy and chemotherapy had a positive effect on survival.


Assuntos
Glioblastoma , Isocitrato Desidrogenase/genética , Proteínas WT1/genética , Proteína Nuclear Ligada ao X/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Mutação , Prognóstico , Estudos Retrospectivos
18.
Adv Cancer Res ; 148: 1-26, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723561

RESUMO

As a unique subpopulation of cancer cells, cancer stem cells (CSCs) acquire the resistance to conventional therapies and appear to be the prime cause of cancer recurrence. Like their normal counterparts, CSCs can renew themselves and generate differentiated progenies. Cancer stem cells are distinguished among heterogenous cancer cells by molecular markers and their capacity of efficiently forming new tumors composed of diverse and heterogenous cancer cells. Tumor heterogeneity can be inter- or intra-tumor, molecularly resulting from the accumulation of genetic and non-genetic alterations. Non-genetic alterations are mainly changes on epigenetic modifications of DNA and histone, and chromatin remodeling. As tumor-initiating cells and contributing to the tumor heterogeneity in the brain, glioblastoma stem cells (GSCs) attract extensive research interests. Epigenetic modifications confer on tumor cells including CSCs reversible and inheritable genomic changes and affect gene expression without alteration in DNA sequence. Here, we will review recent advances in histone demethylation, DNA methylation, RNA methylation and ubiquitination in glioblastomas and their impacts on tumorigenesis with a focus on CSCs.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioblastoma/genética , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Metilação de DNA , Epigênese Genética , Glioblastoma/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo
19.
Nat Commun ; 11(1): 3669, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699356

RESUMO

Recent characterization of spatiotemporal genomic architecture of IDH-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we show two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grow as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues reveals no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 are observed in the subventricular zone (SVZ), but are distantly segregated from multi focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocks distant dispersal, restricting glioma growth in the SVZ.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Evolução Clonal , Evolução Molecular , Glioblastoma/genética , Animais , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Isocitrato Desidrogenase/genética , Cariotipagem , Imagem por Ressonância Magnética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Transgênicos , Mutação , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Transdução de Sinais/genética , Análise de Célula Única , Sequenciamento Completo do Genoma
20.
Nat Commun ; 11(1): 3288, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620753

RESUMO

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Isocitrato Desidrogenase/genética , Proteogenômica/métodos , Proteômica/métodos , Benzamidas/farmacologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase/classificação , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Morfolinas/farmacologia , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia
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