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1.
PLoS Comput Biol ; 16(2): e1007672, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32101537

RESUMO

Glioblastomas are aggressive primary brain tumors known for their inter- and intratumor heterogeneity. This disease is uniformly fatal, with intratumor heterogeneity the major reason for treatment failure and recurrence. Just like the nature vs nurture debate, heterogeneity can arise from intrinsic or environmental influences. Whilst it is impossible to clinically separate observed behavior of cells from their environmental context, using a mathematical framework combined with multiscale data gives us insight into the relative roles of variation from different sources. To better understand the implications of intratumor heterogeneity on therapeutic outcomes, we created a hybrid agent-based mathematical model that captures both the overall tumor kinetics and the individual cellular behavior. We track single cells as agents, cell density on a coarser scale, and growth factor diffusion and dynamics on a finer scale over time and space. Our model parameters were fit utilizing serial MRI imaging and cell tracking data from ex vivo tissue slices acquired from a growth-factor driven glioblastoma murine model. When fitting our model to serial imaging only, there was a spectrum of equally-good parameter fits corresponding to a wide range of phenotypic behaviors. When fitting our model using imaging and cell scale data, we determined that environmental heterogeneity alone is insufficient to match the single cell data, and intrinsic heterogeneity is required to fully capture the migration behavior. The wide spectrum of in silico tumors also had a wide variety of responses to an application of an anti-proliferative treatment. Recurrent tumors were generally less proliferative than pre-treatment tumors as measured via the model simulations and validated from human GBM patient histology. Further, we found that all tumors continued to grow with an anti-migratory treatment alone, but the anti-proliferative/anti-migratory combination generally showed improvement over an anti-proliferative treatment alone. Together our results emphasize the need to better understand the underlying phenotypes and tumor heterogeneity present in a tumor when designing therapeutic regimens.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/fisiopatologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/fisiopatologia , Imagem por Ressonância Magnética , Animais , Proliferação de Células , Biologia Computacional , Simulação por Computador , Humanos , Cinética , Masculino , Camundongos Endogâmicos NOD , Modelos Teóricos , Fenótipo , Ratos , Ratos Sprague-Dawley
2.
PLoS One ; 15(1): e0228030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971966

RESUMO

BACKGROUND: Wavelet transformed reconstructions of dynamic susceptibility contrast (DSC) MR perfusion (wavelet-MRP) are a new and elegant way of visualizing vascularization. Wavelet-MRP maps yield a clear depiction of hypervascular tumor regions, as recently shown. OBJECTIVE: The aim of this study was to elucidate a possible connection of the wavelet-MRP power spectrum in glioblastoma (GBM) with local vascularity and cell proliferation. METHODS: For this IRB-approved study 12 patients (63.0+/-14.9y; 7m) with histologically confirmed IDH-wildtype GBM were included. Target regions for biopsies were prospectively marked on tumor regions as seen on preoperative 3T MRI. During subsequent neurosurgical tumor resection 43 targeted biopsies were taken from these target regions, of which all 27 matching samples were analyzed. All specimens were immunohistochemically analyzed for endothelial cell marker CD31 and proliferation marker Ki67 and correlated to the wavelet-MRP power spectrum as derived from DSC perfusion weighted imaging. RESULTS: There was a strong correlation between wavelet-MRP power spectrum (median = 4.41) and conventional relative cerebral blood volume (median = 5.97 ml/100g) in Spearman's rank-order correlation (κ = .83, p < .05). In a logistic regression model, the wavelet-MRP power spectrum showed a significant correlation to CD31 dichotomized to no or present staining (p = .04), while rCBV did not show a significant correlation to CD31 (p = .30). No significant association between Ki67 and rCBV or wavelet-MRP was found (p = .62 and p = .70, respectively). CONCLUSION: The wavelet-MRP power spectrum derived from existing DSC-MRI data might be a promising new surrogate for tumor vascularity in GBM.


Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Glioblastoma/irrigação sanguínea , Glioblastoma/patologia , Imagem por Ressonância Magnética , Neovascularização Patológica/diagnóstico por imagem , Perfusão , Análise de Ondaletas , Biópsia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/fisiopatologia , Proliferação de Células , Volume Sanguíneo Cerebral , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/fisiopatologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Curva ROC
3.
BMC Neurosci ; 20(1): 63, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870319

RESUMO

BACKGROUND: Autophagy is considered to be another restorative focus for the treatment of brain tumors. Although several research have demonstrated that melatonin induces autophagy in colon cancer and hepatoma cells, there has not been any direct evidence of whether melatonin is capable of inducing autophagy in human glioma cells. RESULTS: In the present research, we report that melatonin or its agonist, agomelatine, induced autophagy in A172 and U87-MG glioblastoma cells for a concentration-and time-dependent way, which was significantly attenuated by treatment with luzindole, a melatonin receptor antagonist. Furthermore, by suppressing autophagy at the late-stage with bafilomycin A1 and early stage with 3-MA, we found that the melatonin-induced autophagy was activated early, and the autophagic flux was complete. Melatonin treatment alone did not induce any apoptotic changes in the glioblastoma cells, as measured by flow cytometry. Western blot studies confirmed that melatonin alone prominently upregulated the levels of Beclin 1 and LC3 II, which was accompanied by an increase in the expression of Bcl-2, whereas it had no effect on the expression of Bax in the glioblastoma cells. Remarkably, co-treatment with 3-MA and melatonin significantly enhanced the apoptotic cell population in the glioblastoma cells, along with a prominent decrease in the expression of bcl-2 and increase in the Bax expression levels, which collectively indicated that the disruption of autophagy triggers the melatonin-induced apoptosis in glioblastoma cells. CONCLUSIONS: These results provide information indicating that melatonin may act as a common upstream signal between autophagy and apoptosis, which may lead to the development of new therapeutic strategies for glioma.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Melatonina/farmacologia , Acetamidas/farmacologia , Apoptose/fisiologia , Autofagia/fisiologia , Neoplasias Encefálicas/fisiopatologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioblastoma/fisiopatologia , Humanos , Macrolídeos/farmacologia , Melatonina/agonistas , Receptores de Melatonina/agonistas , Receptores de Melatonina/antagonistas & inibidores , Triptaminas/farmacologia
5.
Genes Dev ; 33(11-12): 591-609, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31160393

RESUMO

Glioblastoma ranks among the most lethal of all human cancers. Glioblastomas display striking cellular heterogeneity, with stem-like glioblastoma stem cells (GSCs) at the apex. Although the original identification of GSCs dates back more than a decade, the purification and characterization of GSCs remains challenging. Despite these challenges, the evidence that GSCs play important roles in tumor growth and response to therapy has grown. Like normal stem cells, GSCs are functionally defined and distinguished from their differentiated tumor progeny at core transcriptional, epigenetic, and metabolic regulatory levels, suggesting that no single therapeutic modality will be universally effective against a heterogenous GSC population. Glioblastomas induce a systemic immunosuppression with mixed responses to oncoimmunologic modalities, suggesting the potential for augmentation of response with a deeper consideration of GSCs. Unfortunately, the GSC literature has been complicated by frequent use of inferior cell lines and a lack of proper functional analyses. Collectively, glioblastoma offers a reliable cancer to study cancer stem cells to better model the human disease and inform improved biologic understanding and design of novel therapeutics.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Diferenciação Celular , Epigênese Genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Microambiente Tumoral
6.
Mol Med Rep ; 20(2): 1149-1156, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173217

RESUMO

Cell division cycle associated 7 like (CDCA7L) belongs to the JPO protein family, recently identified as a target gene of c­Myc and is frequently dysregulated in multiple cancers. However, to the best of our knowledge, no studies to date have been carried out to investigate the functions of CDCA7L in glioma. Thus, in this study, the expression level of CDCA7L and its association with the prognosis in glioma were detected through the TCGA database. The mRNA expression levels of CDCA7L in glioblastoma (GBM) tissues and normal brain tissues were detected by RT­qPCR and western blot analysis. To explore the role of CDCA7L in glioma, CDCA7L siRNA was constructed and transfected into U87 glioma cells. The expression levels of CDCA7L and cyclin D1 (CCND1) in glioma U87 cells following transfection with CDCA7L siRNA were measured by RT­qPCR and western blot analysis. CCK­8, colony formation, EdU and Transwell assays were used to measure the effects of CDCA7L on U87 cell proliferation, and flow cytometry was used to monitor the changes in the cell cycle following transfection with CDCA7L siRNA. Xenograft tumors were examined in vivo for the carcinogenic effects, as well as the mechanisms and prognostic value of CDCA7L in glioma tissues. The results revealed that CDCA7L was highly expressed in human GBM tissues, and a high expression of CDCA7L was associated with a poor prognosis of glioma patients through the TCGA database. We demonstrated that CDCA7L was highly expressed in human GBM tissues and 3 glioma cell lines. The downregulation CDCA7L expression significantly inhibited the proliferation and colony formation ability of U87 cells by blocking cell cycle progression in the G0/G1 phase. In addition, we found that the mRNA and protein levels of CCND1 were markedly decreased following transfection with CDCA7L siRNA compared with NC siRNA in vitro. The downregulation CDCA7L expression reduced the number of invading cells. Consistent with the results of the in vitro assays, the xenograft assay, immunohistochemistry (IHC) assay and western blot analysis demonstrated that, in response to CDCA7L inhibition, tumor growth was inhibited, Ki­67 and CCND1 expression levels were decreased in vivo. On the whole, the results of the current study indicate that CDCA7L is highly expressed in human glioma tissues and that a high CDCA7L expression predicts a poor prognosis of glioma patients. CDCA7L promotes glioma U87 cell growth through CCND1.


Assuntos
Neoplasias Encefálicas/genética , Proliferação de Células , Ciclina D1/genética , Glioblastoma/genética , Proteínas Repressoras/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/fisiopatologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Math Biosci Eng ; 16(4): 2795-2810, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31137238

RESUMO

This work investigates the mechano-biological features of cells cultured in monolayers in response to different osmotic conditions. In-vitro experiments have been performed to quantify the long-term effects of prolonged osmotic stresses on the morphology and proliferation capacity of glioblastoma cells. The experimental results highlight that both hypotonic and hypertonic conditions affect the proliferative rate of glioblastoma cells on different cell cycle phases. Moreover, glioblastoma cells in hypertonic conditions display a flattened and elongated shape. The latter effect is explained using a nonlinear elastic model for the single cell. Due to a crossover between the free energy contributions related to the cytosol and the cytoskeletal fibers, a critical osmotic stress determines a morphological transition from a uniformly compressed to an elongated shape.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioblastoma/fisiopatologia , Pressão Osmótica , Astrócitos/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Citoesqueleto/metabolismo , Dextranos/química , Elasticidade , Humanos , Microscopia , Modelos Biológicos , Osmose , Pressão , Esferoides Celulares/citologia , Estresse Fisiológico , Resultado do Tratamento
8.
Int J Mol Sci ; 20(10)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117166

RESUMO

Glioblastoma (GBM) is a primary brain tumor whose prognosis is inevitably dismal, leading patients to death in about 15 months from diagnosis. Tumor cells in the mass of the neoplasm are in continuous exchange with cells of the stromal microenvironment, through the production of soluble molecules, among which chemokines play prominent roles. CXCL14 is a chemokine with a pro-tumor role in breast and prostate carcinoma, where it is secreted by cancer associated fibroblasts, and contributes to tumor growth and invasion. We previously observed that CXCL14 expression is higher in GBM tissues than in healthy white matter. Here, we study the effects of exogenously supplemented CXCL14 on key tumorigenic properties of human GBM cell lines. We show that CXCL14 enhances the migration ability and the proliferation of U87MG and LN229 GBM cell lines. None of these effects was affected by the use of AMD3100, an inhibitor of CXCR4 receptor, suggesting that the observed CXCL14 effects are not mediated by this receptor. We also provide evidence that CXCL14 enhances the sphere-forming ability of glioblastoma stem cells, considered the initiating cells, and is responsible for tumor onset, growth and recurrence. In support of our in vitro results, we present data from several GBM expression datasets, demonstrating that CXCL14 expression is inversely correlated with overall survival, that it is enriched at the leading edge of the tumors and in infiltrating tumor areas, and it characterizes mesenchymal and NON G-CIMP tumors, known to have a particularly bad prognosis. Overall, our results point to CXCL14 as a protumorigenic chemokine in GBM.


Assuntos
Movimento Celular , Proliferação de Células , Quimiocinas CXC/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/fisiopatologia , Humanos , Microambiente Tumoral
9.
BMC Med Genomics ; 11(Suppl 7): 34, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894197

RESUMO

BACKGROUND: Recent studies have proposed several gene signatures as biomarkers for different grades of gliomas from various perspectives. However, most of these genes can only be used appropriately for patients with specific grades of gliomas. METHODS: In this study, we aimed to identify survival-relevant genes shared between glioblastoma multiforme (GBM) and lower-grade glioma (LGG), which could be used as potential biomarkers to classify patients into different risk groups. Cox proportional hazard regression model (Cox model) was used to extract relative genes, and effectiveness of genes was estimated against random forest regression. Finally, risk models were constructed with logistic regression. RESULTS: We identified 104 key genes that were shared between GBM and LGG, which could be significantly correlated with patients' survival based on next-generation sequencing data obtained from The Cancer Genome Atlas for gene expression analysis. The effectiveness of these genes in the survival prediction of GBM and LGG was evaluated, and the average receiver operating characteristic curve (ROC) area under the curve values ranged from 0.7 to 0.8. Gene set enrichment analysis revealed that these genes were involved in eight significant pathways and 23 molecular functions. Moreover, the expressions of ten (CTSZ, EFEMP2, ITGA5, KDELR2, MDK, MICALL2, MAP 2 K3, PLAUR, SERPINE1, and SOCS3) of these genes were significantly higher in GBM than in LGG, and comparing their expression levels to those of the proposed control genes (TBP, IPO8, and SDHA) could have the potential capability to classify patients into high- and low- risk groups, which differ significantly in the overall survival. Signatures of candidate genes were validated, by multiple microarray datasets from Gene Expression Omnibus, to increase the robustness of using these potential prognostic factors. In both the GBM and LGG cohort study, most of the patients in the high-risk group had the IDH1 wild-type gene, and those in the low-risk group had IDH1 mutations. Moreover, most of the high-risk patients with LGG possessed a 1p/19q-noncodeletion. CONCLUSION: In this study, we identified survival relevant genes which were shared between GBM and LGG, and those enabled to classify patients into high- and low-risk groups based on expression level analysis. Both the risk groups could be correlated with the well-known genetic variants, thus suggesting their potential prognostic value in clinical application.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Glioblastoma/genética , Glioma/genética , Transcriptoma , Adulto , Idoso , Neoplasias Encefálicas/fisiopatologia , Estudos de Coortes , Feminino , Glioblastoma/fisiopatologia , Glioma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida
10.
Eur Radiol ; 29(10): 5539-5548, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30877463

RESUMO

OBJECTIVES: To test if adding permeability measurement to perfusion obtained from dynamic susceptibility contrast MRI (DSC-MRI) improves diagnostic performance in the differentiation of primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: DSC-MRI was acquired in 145 patients with pathologically proven glioblastoma (n = 89) or PCNSL (n = 56). The permeability metrics of contrast agent extraction fraction (Ex), apparent permeability (Ka), and leakage-corrected perfusion of normalized cerebral blood volume (nCBVres) and cerebral blood flow (nCBFres) were derived from a tissue residue function. For comparison purposes, the leakage-corrected normalized CBV (nCBV) and relative permeability constant (K2) were also obtained using the established Weisskoff-Boxerman leakage correction method. The area under the receiver operating characteristics curve (AUC) and cross-validation were used to compare the diagnostic performance of the single DSC-MRI parameters with the performance obtained with the addition of permeability metrics. RESULTS: PCNSL demonstrated significantly higher permeability (Ex, p < .001) and lower perfusion (nCBVres, nCBFres, and nCBV, all p < .001) than glioblastoma. The combination of Ex and nCBVres showed the highest performance (AUC, 0.96; 95% confidence interval, 0.92-0.99) for differentiating PCNSL from glioblastoma, which was a significant improvement over the single perfusion (nCBV: AUC, 0.84; nCBVres: AUC, 0.84; nCBFres: AUC, 0.82; all p < .001) or Ex (AUC, 0.80; p < .001) parameters. CONCLUSIONS: Analysis of the combined permeability and perfusion metrics obtained from a single DSC-MRI acquisition improves the diagnostic value for differentiating PCNSL from glioblastoma in comparison with single-parameter nCBV analysis. KEY POINTS: • Permeability measurement can be calculated from DSC-MRI with a tissue residue function-based leakage correction. • Adding Exto CBV aids in the differentiation of PCNSL from glioblastoma. • CBV and Exmeasurements from DSC-MRI were highly reproducible.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Linfoma não Hodgkin/diagnóstico por imagem , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/fisiopatologia , Neoplasias do Sistema Nervoso Central/fisiopatologia , Volume Sanguíneo Cerebral/fisiologia , Circulação Cerebrovascular/fisiologia , Meios de Contraste , Diagnóstico Diferencial , Feminino , Glioblastoma/fisiopatologia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Linfoma não Hodgkin/fisiopatologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Perfusão , Permeabilidade , Curva ROC , Estudos Retrospectivos
11.
Theranostics ; 9(5): 1453-1473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867843

RESUMO

Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type. Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM. Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ. However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown. Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6. MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo. Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms. Cu2(OH)PO4@PAA nanoparticles were fabricated through a hydrothermal method. Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo. Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues. MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM. In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target. Notably, photothermal therapy (PTT) mediated by Cu2(OH)PO4@PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM. Simultaneously, the prominent MR imaging (T1WI) ability of Cu2(OH)PO4@PAA could provide visual guidance for PTT. Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Glioblastoma/fisiopatologia , Glioblastoma/terapia , Hipertermia Induzida/métodos , Fototerapia/métodos , Receptores CXCR4/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional , Modelos Animais de Doenças , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Modelos Teóricos , Nanoestruturas/administração & dosagem , Resultado do Tratamento , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Neurooncol ; 143(1): 69-77, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887242

RESUMO

INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2'-hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). METHODS: Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. RESULTS: Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and ß-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. CONCLUSION: Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.


Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Glioblastoma/tratamento farmacológico , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Temozolomida/farmacologia , Acroleína/análogos & derivados , Acroleína/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Benzoatos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Humanos , Camundongos Nus , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Tecidos Suporte
13.
Genes Dev ; 33(9-10): 498-510, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30842215

RESUMO

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/ßcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/ßcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/ßcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of ßcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/ßcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.


Assuntos
Diferenciação Celular/genética , Células-Tronco Neoplásicas/citologia , Transdução de Sinais , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/fisiopatologia , Humanos , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
14.
Neoplasma ; 66(3): 350-356, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30784283

RESUMO

The aberrant expression of microRNA-375 (miR-375) has been proved to be associated with carcinogenesis. However, the role of miR-375 in glioblastoma (GBM) remains unknown. The aim of this study was to investigate biological functions and its molecular mechanisms of miR-375 in GBM cells. In this study, real-time PCR results showed that the level of miR-375 expression in GBM tissues and GBM cell lines (U87 and U251) was decreased. Using MTT assay, Transwell migration and invasion assay, we demonstrated that miR-375 overexpression significantly suppress cell proliferation, cell migration and cell invasion capacity in U87 and U251 cells. However, downregulation of miR-375 had reverse effects on cell proliferation, migration and invasion. Targeting association analysis, dual luciferase assay, RT-PCR and western blot analysis results confirmed that miR-375 could target the 3'UTR of Wnt5a mRNA and regulated its protein expression. Further studies also find overexpression of Wnt5a could significantly reverse miR-375-mediated proliferation, migration and invasion on U87 and U251 cells. Therefore, we concluded that miR-375 inhibited the proliferation and invasion of GBM by regulating Wnt5a and might be a possible therapeutic agent for GBM.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma , MicroRNAs , Invasividade Neoplásica , Proteína Wnt-5a , Adulto , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Glioblastoma/fisiopatologia , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
15.
J Neurooncol ; 142(2): 231-240, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30694423

RESUMO

PURPOSE: Glioblastoma (GBM) is the most common invasive malignant brain tumour in adults. It is traditionally investigated in vitro by culturing cells as a monolayer (2D culture) or as neurospheres (clusters enriched in cancer stem cells) but neither system accurately reflects the complexity of the three-dimensional (3D) chemoresistant microenvironment of GBM. MATERIALS AND METHODS: Using three GBM cell-lines (U87, U251, and SNB19), the effect of culturing cells in a Cultrex-based basement membrane extract (BME) [3D Tumour Growth Assay (TGA)] on morphology, gene expression, metabolism, and temozolomide chemoresistance was investigated. RESULTS: Cells were easily harvested from the 3D model and cultured as a monolayer (2D) and neurospheres. Indeed, the SNB19 cells formed neurospheres only after they were first cultured in the 3D model. The expression of CD133 and OCT4 was upregulated in the neurosphere and 3D assays respectively. Compared with cells cultured in the 2D model, cells were more resistant to temozolomide in the 3D model and this resistance was potentiated by hypoxia. CONCLUSION: Taken together, these results suggest that micro-environmental factors influence GBM sensitivity to temozolomide. Knowledge of the mechanisms involved in temozolomide resistance in this 3D model might lead to the identification of new strategies that enable the more effective use of the current standard of care agents.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Hipóxia Celular , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glioblastoma/tratamento farmacológico , Temozolomida/farmacologia , Antígeno AC133/metabolismo , Neoplasias Encefálicas/fisiopatologia , Técnicas de Cultura de Células , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/fisiopatologia , Humanos , Fator 3 de Transcrição de Octâmero/metabolismo , Tecidos Suporte , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
16.
World Neurosurg ; 123: e303-e309, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30502475

RESUMO

OBJECTIVE: Differentiation of primary central nervous system lymphoma (PCNSL) from glioblastoma using arterial spin labeling perfusion and diffusion tensor imaging (DTI). METHODS: We performed a prospective study of 31 patients with a provisional diagnosis of PCNSL and glioblastoma who underwent conventional magnetic resonance imaging, DTI, and arterial spin labeling of the brain. The tumor blood flow (TBF), mean diffusivity (MD) plus fractional anisotropy (FA) of the mass were measured. The final diagnosis was confirmed by pathological examination. RESULTS: The TBF of PCNSL (26.41 ± 4.03 mL/100 g/minute) was significantly lower than that of glioblastoma (51.08 ± 3.9 mL/100 g/minute; P = 0.001). The TBF cutoff (35.73 mL/100 g/minute) used for differentiation showed area under the curve (AUC) of 0.93, accuracy of 95.2%, sensitivity of 91.7%, and specificity of 100%. The MD of PCNSL (0.87 ± 0.2X 10-3 mm2/second) was significantly lower than that of glioblastoma (0.87 ± 0.2 × 10-3 mm2/second; P = 0.01). The MD cutoff (0.935 × 10-3 mm2/second) used for differentiation showed an AUC of 0.73 and accuracy of 66.7% and a sensitivity of 75% and specificity of 55.6%. The FA of PCNSL (0.253 ± 0.05) was significantly greater than that of glioblastoma (0.135 ± 0.06; P = 0.001). The FA cutoff (0.185) used for differentiation revealed an AUC of 0.944 and accuracy of 85.7% and a sensitivity of 83.3% and specificity of 88.9%. The combined TBF, MD, and FA cutoffs revealed an AUC of 0.96 and accuracy of 95.5% and a sensitivity of 83.3% and specificity of 100%. CONCLUSION: The noninvasive imaging parameters using TBF and DTI might help in differentiating PCNSL from glioblastoma.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Imagem por Ressonância Magnética , Imagem de Perfusão , Adulto , Idoso , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Neoplasias do Sistema Nervoso Central/fisiopatologia , Diagnóstico Diferencial , Feminino , Glioblastoma/fisiopatologia , Humanos , Linfoma/fisiopatologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fluxo Sanguíneo Regional , Sensibilidade e Especificidade
17.
Mol Cell Biochem ; 454(1-2): 11-23, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30251117

RESUMO

Since PI3K/Akt/mTOR and sonic hedgehog (SHH) signaling pathways are highly activated in glioblastoma-initiating cells (GICs), we examined the effects of inhibiting these pathways on GIC characteristics and tumor growth in mice. NVP-LDE-225 (inhibitor of Smoothened) inhibited the expression of Gli1, Gli2, Smoothened, Patched1, and Patched2, and induced the expression of SuFu, whereas NVP-BEZ-235 (dual inhibitor of PI3K and mTOR) inhibited the expression of p-PI3K, p-Akt, p-mTOR, and p-p70S6K. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting the self-renewal capacity of GICs, expression of pluripotency maintaining factors (Nanog, c-Myc, Oct4, and Sox2), Musashi1, cyclin D1, and Bcl-2, and transcription and expression of Gli, and in inducing the expression of cleaved caspase-3, cleaved PARP and Bim. Additionally, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting epithelial-mesenchymal transition. Finally, the combination of NVP-LDE-225 and NVP-BEZ-235 was superior in inhibiting tumor growth, regulating the expression of pluripotency promoting factors, stem cell markers, cell cycle, and cell proliferation, and modulating EMT compared to single agent alone. In conclusion, the combined inhibition of PI3K/Akt/mTOR and SHH pathways was superior to single pathway inhibition in suppressing glioblastoma growth by targeting GICs.


Assuntos
Compostos de Bifenilo/farmacologia , Proliferação de Células , Imidazóis/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Piridinas/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/fisiopatologia , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
18.
J Neurooncol ; 141(2): 303-313, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30535593

RESUMO

INTRODUCTION: The brain is a very soft tissue. Glioblastoma (GBM) brain tumours are highly infiltrative into the surrounding healthy brain tissue and invasion mechanisms that have been defined using rigid substrates therefore may not apply to GBM dissemination. GBMs characteristically lose expression of the high molecular weight tropomyosins, a class of actin-associating proteins and essential regulators of the actin stress fibres and focal adhesions that underpin cell migration on rigid substrates. METHODS: Here, we investigated how loss of the high molecular weight tropomyosins affects GBM on soft matrices that recapitulate the biomechanical architecture of the brain. RESULTS: We find that Tpm 2.1 is down-regulated in GBM grown on soft substrates. We demonstrate that Tpm 2.1 depletion by siRNA induces cell spreading and elongation in soft 3D hydrogels, irrespective of matrix composition. Tpm 1.7, a second high molecular weight tropomyosin is also down-regulated when cells are cultured on soft brain-like surfaces and we show that effects of this isoform are matrix dependent, with Tpm 1.7 inducing cell rounding in 3D collagen gels. Finally, we show that the absence of Tpm 2.1 from primary patient-derived GBMs correlates with elongated, mesenchymal invasion. CONCLUSIONS: We propose that Tpm 2.1 down-regulation facilitates GBM colonisation of the soft brain environment. This specialisation of the GBM actin cytoskeleton organisation that is highly suited to the soft brain-like environment may provide novel therapeutic targets for arresting GBM invasion.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioblastoma/fisiopatologia , Invasividade Neoplásica , Tropomiosina/fisiologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Matriz Extracelular , Técnicas de Silenciamento de Genes , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Hidrogéis , Camundongos , Microscopia de Força Atômica , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Esferoides Celulares/fisiologia , Tropomiosina/genética , Tropomiosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Environ Toxicol ; 34(3): 233-239, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30431227

RESUMO

Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 µM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 µM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 µM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Movimento Celular/efeitos dos fármacos , Flavanonas/farmacologia , Glioblastoma/fisiopatologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica
20.
Eur J Cancer Care (Engl) ; 28(1): e12410, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26531122

RESUMO

The maintenance of quality of life in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme, given its dismal prognosis; thus, the primary aims of treatments are to reduce morbidity, restore or preserve neurological functions, and the capacity to perform daily activities. This review aims to summarise what is currently known about neurocognitive outcome and quality of life in patients with high-grade glioma, particularly in glioblastoma patients. We considered all the variables that can influence neurocognitive functions, the perception of quality of life and their role as predictors for treatment outcomes.


Assuntos
Neoplasias Encefálicas/psicologia , Cognição , Disfunção Cognitiva/psicologia , Glioblastoma/psicologia , Nível de Saúde , Qualidade de Vida/psicologia , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/terapia , Disfunção Cognitiva/fisiopatologia , Glioblastoma/fisiopatologia , Glioblastoma/terapia , Humanos , Prognóstico , Resultado do Tratamento
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