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1.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201962

RESUMO

Sphingosine-1-phosphate (S1P) is a crucial mediator involved in the progression of different cancers, including glioblastoma multiforme (GBM), the most frequent and deadly human brain tumor, characterized by extensive invasiveness and rapid cell growth. Most of GBMs overexpress the epidermal growth factor receptor (EGFR), and we investigated the possible link between S1P and EGFR signaling pathways, focusing on its role in GBM survival, using the U87MG human cell line overexpressing EGFR (EGFR+). We previously demonstrated that EGFR+ cells have higher levels of extracellular S1P and increased sphingosine kinase-1 (SK1) activity than empty vector expressing cells. Notably, we demonstrated that EGFR+ cells are resistant to temozolomide (TMZ), the standard chemotherapeutic drug in GBM treatment, and the inhibition of SK1 or S1P receptors made EGFR+ cells sensitive to TMZ; moreover, exogenous S1P reverted this effect, thus involving extracellular S1P as a survival signal in TMZ resistance in GBM cells. In addition, both PI3K/AKT and MAPK inhibitors markedly reduced cell survival, suggesting that the enhanced resistance to TMZ of EGFR+ cells is dependent on the increased S1P secretion, downstream of the EGFR-ERK-SK1-S1P pathway. Altogether, our study provides evidence of a functional link between S1P and EGFR signaling pathways enhancing the survival properties of GBM cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Humanos , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/metabolismo
2.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206482

RESUMO

Gliomas and glioblastomas are very aggressive forms of brain tumors, prone to the development of a multitude of resistance mechanisms to therapeutic treatments, including cytoprotective autophagy. In this work, we investigated the role and mechanism of action of the combination of a ruthenacarborane derivative with 8-hydroxyquinoline (8-HQ), linked via an ester bond (complex 2), in rat astrocytoma C6 and human glioma U251 cells, in comparison with the two compounds alone, i.e., the free carboxylic acid (complex 1) and 8-HQ, and their non-covalent combination ([1 + 8-HQ], in 1:1 molar ratio). We found that only complex 2 was able to significantly affect cellular viability in glioma U251 cells (IC50 11.4 µM) via inhibition of the autophagic machinery, most likely acting at the early stages of the autophagic cascade. Contrary to 8-HQ alone, complex 2 was also able to impair cellular viability under conditions of glucose deprivation. We thus suggest different mechanisms of action of ruthenacarborane complex 2 than purely organic quinoline-based drugs, making complex 2 a very attractive candidate for evading the known resistances of brain tumors to chloroquine-based therapies.


Assuntos
Antineoplásicos , Astrocitoma , Neoplasias Encefálicas , Complexos de Coordenação , Quinolinas , Rutênio , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Astrocitoma/patologia , Morte Celular Autofágica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Quinolinas/química , Quinolinas/farmacologia , Ratos , Rutênio/química , Rutênio/farmacologia
3.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205043

RESUMO

Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer is urgently needed. Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, three chalcone derivatives were tested regarding their inhibitory activity and selectivity towards GBM cell lines (human and mouse) and a non-cancerous mouse brain cell line. The chalcone 1 showed the most potent and selective cytotoxic effects in the GBM cell lines, being further investigated regarding its ability to reduce critical hallmark features of GBM and to induce apoptosis and cell cycle arrest. This derivative showed to successfully reduce the invasion and proliferation capacity of tumor cells, both key targets for cancer treatment. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was encapsulated into liposomes. Therapeutic concentrations were incorporated retaining the potent in vitro growth inhibitory effect of the selected compound. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Chalconas/farmacologia , Glioblastoma/metabolismo , Animais , Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Lipossomos , Camundongos , Estrutura Molecular , Invasividade Neoplásica
4.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208139

RESUMO

Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro-in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteína da Leucemia Promielocítica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Humanos , Modelos Biológicos , Invasividade Neoplásica , Esferoides Celulares/patologia
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210012

RESUMO

Cancer is one of the most common causes of death worldwide. Along with the advances in diagnostic technology achieved through industry-academia partnerships, the survival rate of cancer patients has improved dramatically through treatments that include surgery, radiation therapy, and pharmacotherapy. This has increased the population of cancer "survivors" and made cancer survivorship an important part of life for patients. The senses of taste and smell during swallowing and cachexia play important roles in dysphagia associated with nutritional disorders in cancer patients. Cancerous lesions in the brain can cause dysphagia. Taste and smell disorders that contribute to swallowing can worsen or develop because of pharmacotherapy or radiation therapy; metabolic or central nervous system damage due to cachexia, sarcopenia, or inflammation can also cause dysphagia. As the causes of eating disorders in cancer patients are complex and involve multiple factors, cancer patients require a multifaceted and long-term approach by the medical care team.


Assuntos
Neoplasias Encefálicas/complicações , Transtornos de Deglutição/metabolismo , Sistema Nervoso/metabolismo , Neoplasias Encefálicas/metabolismo , Transtornos de Deglutição/etiologia , Humanos , Olfato , Paladar
6.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210107

RESUMO

Brain tumors are the most common malignant primary intracranial tumors of the central nervous system. They are often recognized too late for successful therapy. Minimally invasive methods are needed to establish a diagnosis or monitor the response to treatment of CNS tumors. Brain tumors release molecular information into the circulation. Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a substitute for tumor tissue. Tumor-derived biomarkers include nucleic acids, proteins, and tumor-derived extracellular vesicles that accumulate in blood or cerebrospinal fluid. In recent years, circulating tumor cells have also been identified in the blood of glioblastoma patients. In this review of the literature, the authors highlight the significance, regulation, and prevalence of molecular biomarkers such as O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor, and isocitrate dehydrogenase. Herein, we critically review the available literature on plasma circulating tumor cells (CTCs), cell-free tumors (ctDNAs), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) for the diagnosis and monitoring of brain tumor. Currently available markers have significant limitations. While much research has been conductedon these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Células Neoplásicas Circulantes/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Detecção Precoce de Câncer , Vesículas Extracelulares/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Biópsia Líquida , Células Neoplásicas Circulantes/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/genética , Prognóstico
7.
J Med Life ; 14(2): 170-175, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104239

RESUMO

Gangliogliomas are central nervous system tumors located in the temporal lobe of young patients, frequently associated with epilepsy. In this paper, we propose a grading system based solely on histopathological criteria. We reevaluated all cases of ganglioglioma, atypical ganglioglioma, and anaplastic ganglioglioma diagnosed between 2011 and 2020 in the Pathology Department of the Emergency Clinical Hospital Bagdasar-Arseni, based on the type of glial mitoses, the number of neuronal and glial mitoses, presence of necrosis, microvascular proliferation, eosinophilic granular bodies, hypercellularity, presence and disposition of inflammatory infiltrate and atypical pleomorphism. Based on the proposed grading system, a score of 0-4 corresponded to a benign ganglioglioma, 5-9 to an atypical ganglioglioma, and 10-18 to an anaplastic ganglioglioma. The survival rates were 90% for benign ganglioglioma, 71.43% for atypical ganglioglioma, and 62.54% for anaplastic ganglioglioma. One case of benign ganglioglioma underwent a malignant transformation into anaplastic ganglioglioma, and recurrences were noticed in 28.57% of atypical ganglioglioma cases and 30.7% of all anaplastic gangliogliomas. The presence of rare glial mitoses and hypercellularity was correlated with mortality in cases of atypical ganglioglioma. We believe this histopathological scoring system could be used as a three-tier system to identify atypical ganglioglioma cases that are bound to have an aggressive course of evolution and require close follow-up. The other option would be to convert it to a two-tier grading system that can separate low-grade gangliogliomas from high-grade ones. The latter category can encompass both atypical and anaplastic ganglioglioma due to the high mortality of both entities.


Assuntos
Neoplasias Encefálicas/patologia , Ganglioglioma/patologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/metabolismo , Criança , Pré-Escolar , Feminino , Ganglioglioma/complicações , Ganglioglioma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Adulto Jovem
8.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071132

RESUMO

Demethoxycurcumin (DMC), a derivate of curcumin, has been shown to induce apoptotic cell death in human glioblastoma multiforme GBM 8401 cells via cell cycle arrest and induction of cell apoptosis. However, there is no report showing DMC suppresses glioblastoma multiforme cells in vivo. In the present study, we investigated the effects of DMC on GBM8401 cells in vivo. At first, we established a luciferase-expressing stable clone named GBM 8401/luc2. Second, mice were inoculated subcutaneously with GBM 8401/luc2 cells to generate a xenograft tumor mice model. After inoculation, tumor volume reached 100-120 mm3, and all mice were randomly divided into three groups: Group I was treated with 110 µL phosphate-buffered solution (PBS) containing 0.1% dimethyl sulfoxide, Group II with 30 mg/kg of DMC, and Group III with 60 mg/kg of DMC. Mice from each group were given the oral treatment of DMC by gavage for 21 days. The body weight and tumor volume were recorded every 3 days. DMC significantly decreased the tumor volumes, and 60 mg/kg treatment showed a higher decrease in tumor volumes than that of 30 mg/kg, However, DMC did not affect the body weights. The photons emitted from mice tumors were detected with Xenogen IVIS imaging system, DMC at both doses decreased the total photon flux and 60 mg/kg treatment of DMC has low total photon flux than that of 30 mg/kg. The tumor volumes and weights in 60 mg/kg treatment of DMC were lower than that of 30 mg/kg. Immunohistochemical analysis was used to measure protein expression of tumors and results showed that DMC treatment led to lightly staining with anti-Bcl-2 and -XIAP and 60 mg/kg treatment of DMC has lighter staining with anti-Bcl-2 and -XIAP than that of 30 mg/kg. The higher dose (60 mg/kg) of DMC has higher signals of cleaved-caspase-3 than that of the lower dose (30 mg/kg). Furthermore, the hematoxylin and eosin (H&E) staining of liver tissues showed no significant difference between DMC-treated and control-groups. Overall, these observations showed that DMC suppressed tumor properties in vivo and DMC may be used against human glioblastoma multiforme in the future.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Diarileptanoides/uso terapêutico , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Diarileptanoides/toxicidade , Genes Reporter , Glioblastoma/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/análise , Proteínas Proto-Oncogênicas c-bcl-2/análise , Distribuição Aleatória , Carga Tumoral , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/análise , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/análise
9.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067658

RESUMO

Epithelial membrane protein 3 (EMP3) is a tetraspan membrane protein overexpressed in isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma (GBM). Several studies reported high EMP3 levels as a poor prognostic factor in GBM patients. Experimental findings based on glioma and non-glioma models have demonstrated the role of EMP3 in the regulation of several membrane proteins known to drive IDH-wt GBM. In this review, we summarize what is currently known about EMP3 biology. We discuss the regulatory effects that EMP3 exerts on a variety of oncogenic receptors and discuss how these mechanisms may relate to IDH-wt GBM. Lastly, we enumerate the open questions towards EMP3 function in IDH-wt GBM.


Assuntos
Glioblastoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Glioma/genética , Glioma/metabolismo , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Glicoproteínas de Membrana/fisiologia , Prognóstico
10.
Cell Mol Life Sci ; 78(14): 5587-5604, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34100981

RESUMO

To clarify whether differential compartmentalization of Survivin impacts temozolomide (TMZ)-triggered end points, we established a well-defined glioblastoma cell model in vitro (LN229 and A172) and in vivo, distinguishing between its nuclear and cytoplasmic localization. Expression of nuclear export sequence (NES)-mutated Survivin (SurvNESmut-GFP) led to impaired colony formation upon TMZ. This was not due to enhanced cell death but rather due to increased senescence. Nuclear-trapped Survivin reduced homologous recombination (HR)-mediated double-strand break (DSB) repair, as evaluated by γH2AX foci formation and qPCR-based HR assay leading to pronounced induction of chromosome aberrations. Opposite, clones, expressing free-shuttling cytoplasmic but not nuclear-trapped Survivin, could repair TMZ-induced DSBs and evaded senescence. Mass spectrometry-based interactomics revealed, however, no direct interaction of Survivin with any of the repair factors. The improved TMZ-triggered HR activity in Surv-GFP was associated with enhanced mRNA and stabilized RAD51 protein expression, opposite to diminished RAD51 expression in SurvNESmut cells. Notably, cytoplasmic Survivin could significantly compensate for the viability under RAD51 knockdown. Differential Survivin localization also resulted in distinctive TMZ-triggered transcriptional pathways, associated with senescence and chromosome instability as shown by global transcriptome analysis. Orthotopic LN229 xenografts, expressing SurvNESmut exhibited diminished growth and increased DNA damage upon TMZ, as manifested by PCNA and γH2AX foci expression, respectively, in brain tissue sections. Consequently, those mice lived longer. Although tumors of high-grade glioma patients expressed majorly nuclear Survivin, they exhibited rarely NES mutations which did not correlate with survival. Based on our in vitro and xenograft data, Survivin nuclear trapping would facilitate glioma response to TMZ.


Assuntos
Núcleo Celular/metabolismo , Senescência Celular , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Recombinação Homóloga , Survivina/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Biomarcadores Tumorais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Núcleo Celular/genética , Proliferação de Células , Dano ao DNA , Reparo do DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Survivina/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Commun ; 12(1): 3895, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162860

RESUMO

Brain tumors are typically immunosuppressive and refractory to immunotherapies for reasons that remain poorly understood. The unbiased profiling of immune cell types in the tumor microenvironment may reveal immunologic networks affecting therapy and course of disease. Here we identify and validate the presence of hematopoietic stem and progenitor cells (HSPCs) within glioblastoma tissues. Furthermore, we demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes. Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression and display signatures of active cell cycle phases. When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis. In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1 and secretion of tumor promoting cytokines such as IL-6, IL-8 and CCL2, indicating concomitant support of both malignancy and immunosuppression. In patients, the amount of tumor-associated HSPCs in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes. These findings identify an important element in the complex landscape of glioblastoma that may serve as a target for brain tumor immunotherapies.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Cultivadas , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , RNA-Seq/métodos , Transdução de Sinais/genética , Análise de Célula Única/métodos , Microambiente Tumoral/genética
12.
Nat Commun ; 12(1): 3720, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140524

RESUMO

Low levels of reactive oxygen species (ROS) are crucial for maintaining cancer stem cells (CSCs) and their ability to resist therapy, but the ROS regulatory mechanisms in CSCs remains to be explored. Here, we discover that prohibitin (PHB) specifically regulates mitochondrial ROS production in glioma stem-like cells (GSCs) and facilitates GSC radiotherapeutic resistance. We find that PHB is upregulated in GSCs and is associated with malignant gliomas progression and poor prognosis. PHB binds to peroxiredoxin3 (PRDX3), a mitochondrion-specific peroxidase, and stabilizes PRDX3 protein through the ubiquitin-proteasome pathway. Knockout of PHB dramatically elevates ROS levels, thereby inhibiting GSC self-renewal. Importantly, deletion or pharmacological inhibition of PHB potently slows tumor growth and sensitizes tumors to radiotherapy, thus providing significant survival benefits in GSC-derived orthotopic tumors and glioblastoma patient-derived xenografts. These results reveal a selective role of PHB in mitochondrial ROS regulation in GSCs and suggest that targeting PHB improves radiotherapeutic efficacy in glioblastoma.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Adulto , Idoso , Animais , Astrocitoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Inativação de Genes , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Gradação de Tumores , Peroxirredoxinas/metabolismo , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065977

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor, and macrophages account for 30-40% of its composition. Most of these macrophages derive from bone marrow monocytes playing a crucial role in tumor progression. Unraveling the mechanisms of macrophages-GBM crosstalk in an appropriate model will contribute to the development of specific and more successful therapies. We investigated the interaction of U87MG human GBM cells with primary human CD14+ monocytes or the THP-1 cell line with the aim of establishing a physiologically relevant heterotypic culture model. METHODS: primary monocytes and THP-1 cells were cultured in the presence of U87MG conditioned media or co-cultured together with previously formed GBM spheroids. Monocyte differentiation was determined by flow cytometry. RESULTS: primary monocytes differentiate to M2 macrophages when incubated with U87MG conditioned media in 2-dimensional culture, as determined by the increased percentage of CD14+CD206+ and CD64+CD206+ populations in CD11b+ cells. Moreover, the mitochondrial protein p32/gC1qR is expressed in monocytes exposed to U87MG conditioned media. When primary CD14+ monocytes or THP-1 cells are added to previously formed GBM spheroids, both invade and establish within them. However, only primary monocytes differentiate and acquire a clear M2 phenotype characterized by the upregulation of CD206, CD163, and MERTK surface markers on the CD11b+CD14+ population and induce alterations in the sphericity of the cell cultures. CONCLUSION: our results present a new physiologically relevant model to study GBM/macrophage interactions in a human setting and suggest that both soluble GBM factors, as well as cell-contact dependent signals, are strong inducers of anti-inflammatory macrophages within the tumor niche.


Assuntos
Neoplasias Encefálicas/metabolismo , Técnicas de Cocultura/métodos , Glioblastoma/metabolismo , Macrófagos/citologia , Monócitos/citologia , Biomarcadores/metabolismo , Proteínas de Transporte/metabolismo , Comunicação Celular , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas Mitocondriais/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Cultura Primária de Células , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Células THP-1
14.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065991

RESUMO

Although there are many patients with brain tumors worldwide, there are numerous difficulties in overcoming brain tumors. Among brain tumors, glioblastoma, with a 5-year survival rate of 5.1%, is the most malignant. In addition to surgical operations, chemotherapy and radiotherapy are generally performed, but the patients have very limited options. Temozolomide is the most commonly prescribed drug for patients with glioblastoma. However, it is difficult to completely remove the tumor with this drug alone. Therefore, it is necessary to discuss the potential of anticancer drugs, other than temozolomide, against glioblastomas. Since the discovery of cisplatin, platinum-based drugs have become one of the leading chemotherapeutic drugs. Although many studies have reported the efficacy of platinum-based anticancer drugs against various carcinomas, studies on their effectiveness against brain tumors are insufficient. In this review, we elucidated the anticancer effects and advantages of platinum-based drugs used in brain tumors. In addition, the cases and limitations of the clinical application of platinum-based drugs are summarized. As a solution to overcome these obstacles, we emphasized the potential of a novel approach to increase the effectiveness of platinum-based drugs.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Compostos de Platina/uso terapêutico , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Compostos de Platina/farmacologia , Análise de Sobrevida , Resultado do Tratamento
15.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073734

RESUMO

Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioma/metabolismo , Glicólise , Ácido Láctico/metabolismo , Microambiente Tumoral , Animais , Química Encefálica , Neoplasias Encefálicas/fisiopatologia , Anidrases Carbônicas , Glioma/fisiopatologia , Humanos , Concentração de Íons de Hidrogênio , Neovascularização Patológica
16.
Neuroreport ; 32(9): 771-775, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-33994523

RESUMO

Since coronavirus disease 2019 (COVID-19) swept all over the world, several studies have shown the susceptibility of a patient with cancer to COVID-19. In this case, the removed glioblastoma multiforme (GBM)-adjacent (GBM-A), GBM-peritumor and GBM-central (GBM-C) tissues from a convalescent patient of COVID-19, who also suffered from glioblastoma meanwhile, together with GBM-A and GBM tissues from a patient without COVID-19 history as negative controls, were used for RNA ISH, electron microscopy observing and immunohistochemical staining of ACE2 and the virus antigen (N protein). The results of RNA ISH, electron microscopy observing showed that SARS-CoV-2 directly infects some cells within human GBM tissues and SARS-CoV-2 in GBM-C tissue still exists even when it is cleared elsewhere. Immunohistochemical staining of ACE2 and N protein showed that the expressions of ACE2 are significantly higher in specimens, including GBM-C tissue from COVID-19 patient than other types of tissue. The unique phenomenon suggests that the surgical protection level should be upgraded even if the patient is in a convalescent period and the pharyngeal swab tests show negative results. Furthermore, more attention should be paid to confirm whether the shelter-like phenomenon happens in other malignancies due to the similar microenvironment and high expression of ACE2 in some malignancies.


Assuntos
Neoplasias Encefálicas/virologia , COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Glioblastoma/virologia , SARS-CoV-2/metabolismo , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/ultraestrutura , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19 , Convalescença , Glioblastoma/metabolismo , Glioblastoma/cirurgia , Glioblastoma/ultraestrutura , Humanos , Hibridização In Situ , Masculino , Microscopia Eletrônica de Transmissão , Fosfoproteínas/metabolismo , RNA Viral/metabolismo , Receptores de Coronavírus/metabolismo , SARS-CoV-2/ultraestrutura , Vírion/ultraestrutura
17.
Mol Biol Rep ; 48(4): 3495-3502, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34003424

RESUMO

Glioblastoma multiform is a primary brain tumor derived from glial cells. The aim of this study is to investigate how glutamate metabolism is regulated by glutamate transporter 1 (GLT-1) degradation pathway in glioblastoma and glial cell lines. The protein expression levels of GLT-1, total ubiquitin, protein kinase C (PKC) proteins involved in the GLT-1 degradation pathway were measured by the western blot technique. Additionally, in glial and glioblastoma cells, the level of glutamate accumulated in the medium and the lysates was measured with the glutamate assay. GLT-1 protein expression was increased significantly in glioblastoma cells. The expression levels of the PKC protein and total ubiquitin were found to be decreased in glioblastoma cells although not significantly. The glutamate accumulated in the medium and lysates of glioblastoma cells is reduced compared to glial cells. Further research regarding excitotoxicity in glioblastoma focusing on GLT-1 degradation or activation pathway may create new opportunities of drug and treatment development.


Assuntos
Neoplasias Encefálicas/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Glioblastoma/metabolismo , Linhagem Celular Tumoral , Ácido Glutâmico/metabolismo , Humanos , Proteólise , Ubiquitina/metabolismo
18.
J Cancer Res Clin Oncol ; 147(8): 2271-2280, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33963441

RESUMO

PURPOSE: Gliomas are the most frequent primary brain tumors of adults. Despite intensive research, there are still no targeted therapies available. Here, we performed an integrated analysis of glioma and programmed cell death ligand 1 (PD-L1) in 90 samples including 58 glioma and 32 control brain tissues. METHODS: To identify PD-L1 expression in glioma, we performed immunohistochemical analysis of PD-L1 tumor proportion score (TPS) using the clinically valid PD-L1 22C3 antibody on 90 samples including controls and WHO grade I-IV gliomas. RESULTS: We found that PD-L1 is highly expressed in a subfraction of glioma cells. Analysis of PD-L1 levels in different glioma subtypes revealed a strong intertumoral variation of PD-L1 protein. Furthermore, we correlated PD-L1 expression with molecular glioma hallmarks such as MGMT-promoter methylation, IDH1/2 mutations, TERT promoter mutations and LOH1p/19q. CONCLUSION: In summary, we found that PD-L1 is highly expressed in a subfraction of glioma, indicating PD-L1 as a potential new marker in glioma assessment opening up novel therapeutic approaches.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Feminino , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Adulto Jovem
19.
Aging (Albany NY) ; 13(9): 13287-13299, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33982667

RESUMO

BACKGROUND: Glioma is one of the most wide-spreading brain cancers worldwide. Exosomes have emerged as essential regulators in intercellular communication, and exosomal circular RNAs (circRNAs) are critical for cancer progression. In this study, we aimed to investigate the role of exosomal circRNAs in glioma progression and associated mechanisms. METHODS: Exosomes derived from glioma cells were isolated and identified by transmission electron microscopy and nanoparticle tracking analysis (NTA). CCK-8, wound healing assays, transwell invasion assays, and flow cytometry assays were performed to assess glioma progression. RNA sequencing, RT-qPCR, western blotting, fluorescence in situ hybridization assay, luciferase assays, and cell transfection assay were performed to investigate related molecular mechanisms. RESULTS: The results demonstrated that exosomes derived from glioma cells promoted glioma progression. Also, exosomal circRNA 0001445 was taken up and upregulated in glioma cells treated with exosomes. In addition, exosomal circRNA 0001445 acted as a sponge for miRNA-127-5p to upregulate the expression of sorting nexin 5 (SNX5). Lastly, the effect of exosomal circRNA 0001445 was mediated by miRNA-127-5p/ SNX5 signaling pathway. CONCLUSION: These results demonstrated that exosomal circRNA 0001445 promoted glioma progression through miRNA-127-5p/SNX5 signaling pathway. This study provides a novel understanding of the molecular mechanism of glioma progression.


Assuntos
Neoplasias Encefálicas/genética , Exossomos/metabolismo , Glioma/metabolismo , RNA Circular/sangue , Neoplasias Encefálicas/metabolismo , Movimento Celular/fisiologia , Glioma/sangue , Glioma/genética , Humanos , Análise de Sequência de RNA/métodos , Nexinas de Classificação/metabolismo
20.
Turk Neurosurg ; 31(3): 447-459, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33978213

RESUMO

AIM: To analyze the Glutathione S-transferase (GST)-P, GST-M, cytochrome p450 (CYP)1-A1, CYP1-B1, and multidrug resistance (MDR)-1 expressions in malignant intracranial tumor (ICT)s, and to elicit their role on patient survival. MATERIAL AND METHODS: GST-P, GST-M, CYP1-A1, CYP1-B1, and MDR-1 expressions were analyzed using immunostaining in 149 samples from 141 patients with preoperative ICT diagnosis. The case characteristics were reviewed, and the enzyme expressions were equated based on the age, gender, and tumor type. Then, 77 of 141 patients with malignant ICT and complete medical records postoperative were also investigated in detail for the relationship between the diagnosis, enzyme expression, and overall survival. RESULTS: The average age was 49.44 years, with 83 (58.45%) male patients. Among the 77 malignant ICTs, 38 (49.3%) and 29 were glial tumors and metastases, respectively, with a 13.35-month overall survival. Patients with metastatic tumor have approximately threefold higher GSTP level than those with glial tumors. MDR-1 expression was approximately twofold higher in > 60-year-old patients. No statistically significant association was found between patients? smoking behaviors, alcohol consumption, and overall survival. Only MDR-1 expression was correlated with overall survival. Better overall survival was observed in patients with a negative MDR-1 expression than those with a positive one. CONCLUSION: MDR-1 is an important indicator of survival in malignant intracranial tumor patients. Longer survival is associated with negative MDR-1 expression.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glutationa Transferase/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto Jovem
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