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1.
Semin Cell Dev Biol ; 133: 32-41, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35697594

RESUMO

Extracellular vesicles (EVs) are membrane-delimited vesicular bodies carrying different molecules, classified according to their size, density, cargo, and origin. Research on this topic has been actively growing through the years, as EVs are associated with critical pathological processes such as neurodegenerative diseases and cancer. Despite that, studies exploring the physiological functions of EVs are sparse, with particular emphasis on their role in organismal development, initial cell differentiation, and morphogenesis. In this review, we explore the topic of EVs from a developmental perspective, discussing their role in the earliest cell-fate decisions and neural tissue morphogenesis. We focus on the function of EVs through development to highlight possible conserved or novel processes that can impact disease progression. Specifically, we take advantage of what was learned about their role in development so far to discuss EVs impact on glioblastoma, a particular brain tumor of stem-cell origin and poor prognosis, and how their function can be hijacked to improve current therapies.


Assuntos
Vesículas Extracelulares , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Vesículas Extracelulares/patologia , Comunicação Celular , Células-Tronco , Diferenciação Celular
2.
Methods Mol Biol ; 2572: 117-127, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36161412

RESUMO

Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Experimentais , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Organoides/patologia , Microambiente Tumoral
3.
Mol Med Rep ; 27(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36367159

RESUMO

Glioblastoma is one of the most frequent primary brain tumors with a poor prognosis. Nevertheless, some patients show a prolonged survival. The aim of the present study was to compare the expression profiles of tumor derived microRNA (miR) of long­term survivors with those of short­term survivors in order to identify differentially expressed miRs as well as their target genes, which may elucidate mechanisms that play a role in varying tumor progression and, therefore, may influence survival. Formalin­fixed paraffin­embedded samples of 23 patients with glioblastoma were classified according to overall survival. Profiles of miR expression were determined using Nanostring technology. Expression levels of potential target genes of differentially expressed miRs were assessed using immunohistochemistry. MiR profiles of long­term survivors differed from those of short­term survivors. A total of three prominent differentially expressed miRs were highlighted: MiR­130b­3p, which is downregulated in long­term survivors, and miR­146b­5p and miR­148a­3p, which are upregulated in long­term survivors. Known tumor suppressor genes are among targets potentially affected by miR­130b­3p, whereas targets of miR­146b­5p and miR­148a­3p consist of several genes known to have a role in tumor invasion and aggressiveness. In conclusion, it was revealed that a type of miR­signature was associated with short­ and long­term survival, potentially serving as biomarker for disease progression and providing a base for further functional studies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , MicroRNAs , Humanos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , MicroRNAs/genética , MicroRNAs/metabolismo
4.
Phytomedicine ; 108: 154492, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36257220

RESUMO

BACKGROUND: Cancer stem cells (CSCs) are characterized by their ability to self-renew, to differentiate into multiple cell types and also drive tumor formation, altogether making them important cellular targets for therapeutic intervention. However, existing CSC-targeting drugs do not significantly improve clinical outcomes. More recently, preclinical studies of natural product-derived compounds have demonstrated their potential usefulness as a therapeutic cancer treatment through their cytotoxic actions on CSCs. PURPOSE: Here, we identify CSC-specific compounds derived from natural products and characterize their putative mechanisms of action in CSCs. METHODS: Glioblastoma stem cells (GSCs) were labeled with EGFP via homologous recombination and utilized for a high-throughput screen of 8,344 fractions from 386 herbal medicines. The fractions that extinguished EGFP fluorescence signal were then further characterized by LC-MS/MS. Next, several putative cytotoxic compounds were evaluated for their cytotoxic effects on GSCs, cancer cell lines and immortalized cells using a variety of methods to study cell proliferation (EdU incorporation assay), cell death (cleaved-Caspase-3 immunostaining), DNA damage (comet assay), mitochondrial membrane changes (JC-1 immunostaining), and tumor formation in vitro (soft agar colony forming assay). We also performed surface plasmon resonance analysis, western blotting, and immunohistochemistry to characterize the putative mechanisms underlying the cytotoxic effects of putative compounds on GSCs. Finally, we carried out xenograft tumor growth assays to study the cytotoxic potential of several candidates in vivo. RESULTS: Our high throughput screen led to the identification of the furostanol saponin taccaoside A and its two homologs from the rhizomatous geophyte Tacca. subflabellata that were cytotoxic to GSCs. Interestingly, the cytotoxic effect of taccaoside A on cell lines was significantly less compared to its homologs, owing to stereochemical differences of a carbon-carbon double bond between C-20 and C-22. Molecular studies revealed that taccaoside A binds to RAS to inhibit downstream effector signaling. Correspondingly, blockade of the interaction between taccaoside A and RAS abolished the inhibitory effect of this compound on CSCs. Furthermore, taccaoside A treatment was effective in limiting tumor cell growth in vivo. CONCLUSION: Our study yielded an effective approach to screen for CSC-specific agents. Through this approach, we identified taccaoside A from the rhizomatous geophyte Tacca. subflabellata are cytotoxic to CSCs through a molecular mechanism that involves RAS binding and suppression of its downstream signaling. Our findings indicate taccaoside A is a potential lead compound for anti-CSC drug discovery.


Assuntos
Antineoplásicos , Glioblastoma , Humanos , Cromatografia Líquida , Detecção Precoce de Câncer , Espectrometria de Massas em Tandem , Células-Tronco Neoplásicas , Antineoplásicos/farmacologia , Proliferação de Células , Glioblastoma/patologia , Carbono/metabolismo , Carbono/farmacologia , Linhagem Celular Tumoral
5.
Pathol Res Pract ; 240: 154187, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36327821

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor. It has a poor 5-year survival rate, a high recurrence rate, and few therapeutic options. Exploring the molecular processes underlying the formation and progression of GBM, as well as identifying novel therapeutic targets, is critical for improving GBM therapy and prognosis. METHODS: We extracted primary GSCs (glioblastoma stem cells) from patient-derived samples. Different levels of CSNK1D were evaluated through immunohistochemistry, western blot and real-time PCR assays. A Transwell assay was used to detect invasive ability of cell lines. Tumorsphere formation assay was performed to detect cancer stemness properties. Orthotopic xenograft models were used to evaluate the effect of CSNK1D on GSC tumorigenesis. RESULTS: We found the expression levels of CSNK1D was elevated in GBM tissues compared with normal brain. CSNK1D expression had an increased tendency among WHO grades (G2-G4), and was higher in IDH wildtype group than in mutation group. The prognosis of the CSNK1D high expression group was significantly worse than that of the low expression group. Cox multivariate analysis showed that CSNK1D was also an independent prognostic factor in GBM patients. In primary GBM cells, we observed increased levels of CSNK1D in GSCs compared to non-stem tumor cells (NSTCs). In addition, the change of stemness markers expression and proliferation of GSCs were in coordinate with CSNK1D overexpression or knockdown. Furthermore, CSNK1D could affect the epithelial-mesenchymal transition (EMT) markers and MMPs expression in GSCs. Finally, disruption of CSNK1D expression impairs GSC survival and GBM tumor propagation in orthotopic xenograft models. CONCLUSION: Our results suggest that CSNK1D correlated with GBM prognosis and might influence the stemness and invasiveness of GSCs, which represented a potential therapeutic target in GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Transição Epitelial-Mesenquimal , Carcinogênese/metabolismo , Prognóstico , Células-Tronco Neoplásicas/patologia , Neoplasias Encefálicas/patologia , Proliferação de Células , Linhagem Celular Tumoral
6.
J Neurol Sci ; 443: 120488, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36368135

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain cancer. Drug-resistant seizures and cognitive impairments often accompany the invasion of the neocortex by the GBM cells. Recent studies suggest that seizures and glioma share common pathogenic mechanisms and may influence each other. One explanation for the close link between the two conditions is elevated glutamate in the tumor microenvironment (TME) due to an increased expression of the cystine-glutamate transporter with ensuing overactivity of glutamatergic signaling. Excess glutamate in the TME also encourages the polarization of pro-inflammatory tumor-associated macrophages to an anti-inflammatory state causing TME immunosuppression and facilitating tumor invasion. Besides, the recently discovered glutamatergic neurogliomal synapses, partially via their influence on calcium communication in microtube-connected tumor cell networks, drive the progression of GBM by stimulating glioma invasion and growth. Moreover, neuroinflammatory pathways have been shown to have several points of intersection with glutamatergic signaling in the TME, further promoting both epileptogenesis and oncogenesis. Future studies identifying pharmacotherapeutics targeting these elements is an extremely attractive therapeutic strategy for GBM, for which very little therapeutic progress has been made in the past two decades.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Glioma/metabolismo , Ácido Glutâmico/metabolismo , Convulsões , Microambiente Tumoral
7.
J Control Release ; 352: 623-636, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36349615

RESUMO

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.


Assuntos
Antineoplásicos , Glioblastoma , Pró-Fármacos , Humanos , Animais , Camundongos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Cisplatino , Pró-Fármacos/uso terapêutico , Platina , Camundongos Nus , Peptídeos/uso terapêutico , Encéfalo , Resultado do Tratamento , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Linhagem Celular Tumoral
8.
Sci Rep ; 12(1): 19744, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396681

RESUMO

Survival prediction models can potentially be used to guide treatment of glioblastoma patients. However, currently available MR imaging biomarkers holding prognostic information are often challenging to interpret, have difficulties generalizing across data acquisitions, or are only applicable to pre-operative MR data. In this paper we aim to address these issues by introducing novel imaging features that can be automatically computed from MR images and fed into machine learning models to predict patient survival. The features we propose have a direct anatomical-functional interpretation: They measure the deformation caused by the tumor on the surrounding brain structures, comparing the shape of various structures in the patient's brain to their expected shape in healthy individuals. To obtain the required segmentations, we use an automatic method that is contrast-adaptive and robust to missing modalities, making the features generalizable across scanners and imaging protocols. Since the features we propose do not depend on characteristics of the tumor region itself, they are also applicable to post-operative images, which have been much less studied in the context of survival prediction. Using experiments involving both pre- and post-operative data, we show that the proposed features carry prognostic value in terms of overall- and progression-free survival, over and above that of conventional non-imaging features.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Imageamento por Ressonância Magnética/métodos , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Prognóstico
9.
Acta Med Okayama ; 76(5): 489-502, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36352795

RESUMO

Glioblastoma (GBM) is a fatal primary malignant brain tumor in adults. Despite decades of research, the prognosis for GBM patients is still disappointing. One major reason for the intense therapeutic resistance of GBM is inter- and intra-tumor heterogeneity. GBM-intrinsic transcriptional profiling has suggested the presence of at least three subtypes of GBM: the proneural, classic, and mesenchymal subtypes. The mesenchymal subtype is the most aggressive, and patients with the mesenchymal subtype of primary and recurrent tumors tend to have a worse prognosis compared with patients with the other subtypes. Furthermore, GBM can shift from other subtypes to the mesenchymal subtype over the course of disease progression or recurrence. This phenotypic transition is driven by diverse tumor-intrinsic molecular mechanisms or microenvironmental factors. Thus, better understanding of the plastic nature of mesenchymal transition in GBM is pivotal to developing new therapeutic strategies. In this review, we provide a comprehensive overview of the current understanding of the elements involved in the mesenchymal transition of GBM and discuss future perspectives.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Prognóstico , Regulação Neoplásica da Expressão Gênica
10.
Medicine (Baltimore) ; 101(45): e31418, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397358

RESUMO

Glioblastoma (GBM) is a malignant tumor. The long-term prognosis of the patients is poor. Therefore, it is of important clinical value to further explore the pathogenesis and look for molecular markers for early diagnosis and targeted treatment. Two expression profiling datasets [GSE50161 (GPL570 platform), GSE116520 (GPL10558 platform)] were respectively downloaded from the gene expression omnibus database. Volcano diagrams show the Differently expressed genes (DEGs) of GSE50161 and GSE116520. A Venn diagram revealed 467 common DEGs between the 2 datasets. Lysyl oxidase (LOX), serpin family H member 1 (SERPINH1) and transforming growth factor beta induced (TGFBI) were negatively correlated with the overall survival rate in patients with GBM. The hub genes are high in GBM tumor tissues. The relative expression levels of LOX, SERPINH1 and TGFBI were significantly higher in GBM samples, compared with the normal brain tissues groups. Bioinformatics technology could be a useful tool to predict progression of GBM and to explore the mechanism of GBM.LOX, SERPINH1 and TGFBI may be involved in the mechanism of the occurrence and development of GBM, and may be used as molecular targets for early diagnosis and specific treatment. DEGs identified using GEO2R. Functional annotation of DEGs using Kyoto Encyclopedia of Genes and Genomes and gene body pathway enrichment analysis. Construction of a protein-protein interaction network. The pathway and process enrichment analysis of the hub genes were performed by Metascape. Survival analysis was performed in gene expression profiling interactive analysis. Real-time fluorescent quantitative polymerase chain reaction assay was performed to verify. The animal model was established for western blot test analysis.


Assuntos
Glioblastoma , Humanos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Glioblastoma/patologia , Proteínas de Choque Térmico HSP47/genética , Proteínas de Choque Térmico HSP47/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
11.
Elife ; 112022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36412091

RESUMO

We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Adulto , Glioblastoma/patologia , Neoplasias Encefálicas/genética , Astrócitos/metabolismo , Metilação de DNA , Epigenômica
12.
Int J Mol Sci ; 23(22)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36430641

RESUMO

Glioblastoma is refractory to therapy and presents a significant oncological challenge. Promising immunotherapies have not shown the promise observed in other aggressive cancers. The reasons for this include the highly immuno-suppressive tumour microenvironment controlled by the glioblastoma cells and heterogeneous phenotype of the glioblastoma cells. Here, we wanted to better understand which glioblastoma phenotypes produced the regulatory cytokines, particularly those that are implicated in shaping the immune microenvironment. In this study, we employed nanoString analysis of the glioblastoma transcriptome, and proteomic analysis (proteome profiler arrays and cytokine profiling) of secreted cytokines by different glioblastoma phenotypes. These phenotypes were cultured to reflect a spectrum of glioblastoma cells present in tumours, by culturing an enhanced stem-like phenotype of glioblastoma cells or a more differentiated phenotype following culture with serum. Extensive secretome profiling reveals that there is considerable heterogeneity in secretion patterns between serum-derived and glioblastoma stem-like cells, as well as between individuals. Generally, however, the serum-derived phenotypes appear to be the primary producers of cytokines associated with immune cell recruitment into the tumour microenvironment. Therefore, these glioblastoma cells have considerable importance in shaping the immune landscape in glioblastoma and represent a valuable therapeutic target that should not be ignored.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Citocinas/genética , Neoplasias Encefálicas/patologia , Proteômica , Fenótipo , Microambiente Tumoral
13.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430704

RESUMO

Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma.


Assuntos
Astrocitoma , Glioblastoma , Glioma , Oligodendroglioma , Humanos , Glioma/genética , Glioma/terapia , Glioma/patologia , Oligodendroglioma/patologia , Glioblastoma/patologia , Astrocitoma/patologia , Células-Tronco Neoplásicas/patologia
14.
Cell Stem Cell ; 29(11): 1509-1510, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36332566

RESUMO

Glioblastomas are lethal malignancies that possess a rapidly evolving microenvironment containing necrotic/hypoxic areas, aberrant microvasculature, and glioblastoma stem cells (GSCs) that promote tumor growth, recurrence, and treatment resistance. Chen et al. find that GSCs drive integrated epigenetic and metabolic control of angiogenesis via histamine and propose antihistamines as potential therapies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Neoplasias Encefálicas/patologia , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral
15.
Acta Neuropathol Commun ; 10(1): 159, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333778

RESUMO

A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan-Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Neoplasias Encefálicas/patologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Metilação de DNA , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Fenótipo , Células-Tronco/metabolismo
16.
Nat Commun ; 13(1): 6835, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369424

RESUMO

Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival.


Assuntos
Glioblastoma , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Nanogéis , Biomimética , Temozolomida , Verde de Indocianina , Linhagem Celular Tumoral
17.
Cell Death Dis ; 13(11): 943, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351894

RESUMO

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, but the mechanisms underlying tumor growth and progression remain unclear. The protein arginine methyltransferases (PRMTs) regulate a variety of biological processes, however, their roles in GBM growth and progression are not fully understood. In this study, our functional analysis of gene expression networks revealed that among the PRMT family expression of PRMT3 was most significantly enriched in both GBM and low-grade gliomas. Higher PRMT3 expression predicted poorer overall survival rate in patients with gliomas. Knockdown of PRMT3 markedly reduced the proliferation and migration of GBM cell lines and patient-derived glioblastoma stem cells (GSC) in cell culture, while its over-expression increased the proliferative capacity of GSC cells by promoting cell cycle progression. Consistently, stable PRMT3 knockdown strongly inhibited tumor growth in xenograft mouse models, along with a significant decrease in cell proliferation as well as an increase in apoptosis. We further found that PRMT3 reprogrammed metabolic pathways to promote GSC growth via increasing glycolysis and its critical transcriptional regulator HIF1α. In addition, pharmacological inhibition of PRMT3 with a PRMT3-specific inhibitor SGC707 impaired the growth of GBM cells. Thus, our study demonstrates that PRMT3 promotes GBM progression by enhancing HIF1A-mediated glycolysis and metabolic rewiring, presenting a point of metabolic vulnerability for therapeutic targeting in malignant gliomas.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Camundongos , Animais , Glioblastoma/genética , Glioblastoma/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Glicólise/genética , Proliferação de Células/genética , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
18.
Int J Mol Sci ; 23(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36361947

RESUMO

Microglial cells represent the resident immune elements of the central nervous system, where they exert constant monitoring and contribute to preserving neuronal activity and function. In the context of glioblastoma (GBM), a common type of tumor originating in the brain, microglial cells deeply modify their phenotype, lose their homeostatic functions, invade the tumoral mass and support the growth and further invasion of the tumoral cells into the surrounding brain parenchyma. These modifications are, at least in part, induced by bidirectional communication among microglial and tumoral cells through the release of soluble molecules and extracellular vesicles (EVs). EVs produced by GBM and microglial cells transfer different kinds of biological information to receiving cells, deeply modifying their phenotype and activity and could represent important diagnostic markers and therapeutic targets. Recent evidence demonstrates that in GBM, microglial-derived EVs contribute to the immune suppression of the tumor microenvironment (TME), thus favoring GBM immune escape. In this review, we report the current knowledge on EV formation, biogenesis, cargo and functions, with a focus on the effects of microglia-derived EVs in GBM. What clearly emerges from this analysis is that we are at the beginning of a full understanding of the complete picture of the biological effects of microglial-derived EVs and that further investigations using multidisciplinary approaches are necessary to validate their use in GBM diagnosis and therapy.


Assuntos
Neoplasias Encefálicas , Vesículas Extracelulares , Glioblastoma , Humanos , Microglia/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Vesículas Extracelulares/genética , Microambiente Tumoral , Encéfalo/patologia
19.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362294

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma.


Assuntos
Diabetes Mellitus Tipo 2 , Glioblastoma , Glioma , Tiazolidinedionas , Animais , PPAR gama/metabolismo , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Glioma/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Proteínas Associadas aos Microtúbulos , Linhagem Celular Tumoral
20.
J Cancer Res Ther ; 18(6): 1616-1622, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412420

RESUMO

Background: Malignant transformation (MT) of low-grade astrocytoma (LGA) produces a poor prognosis in benign tumors. Currently, variables linked with MT of LGA have proven equivocal. The present study aims to evaluate the risk variables, indicating that LGA gradually differentiates to malignant astrocytoma. Methods: Retrospective cohort analysis of LGA patients was performed. Both univariate and multivariate studies were used to discover variables connected to MT using the Cox regression method. As a result, the cumulative incidence of MT for each covariate survival curve was built after the final model. Results: In the current study, 115 individuals with LGA were included in the analysis, and MT was found in 16.5% of cases. In the case of MT, 68.4% of patients progressed to glioblastoma, whereas 31.6% progressed to anaplastic astrocytoma. Significant factors included supratentorial tumor (hazard ratio (HR) 3.41, 95% CI 1.18-12.10), midline shift > 5 mm (HR 7.15, 95% CI 2.28-34.33), and non-total resection as follows: subtotal resection (HR 5.09, 95% CI 0.07-24.02), partial resection (HR 1.61, 95% CI 1.09-24.11), and biopsy (HR 2.80, 95% CI 1.18-32.52). Conclusion: In individuals with LGA, MT dramatically altered the disease's natural history to a poor prognosis. The present study's analysis of the clinical features of patients indicated supratentorial LGA, a midline shift greater than 5 mm, and the degree of resection as risk factors for MT. The more extensive the resection, the greater the reduction in tumor load and MT. In addition, more molecular study is necessary to elucidate the pathophysiology of MT.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Humanos , Estudos Retrospectivos , Neoplasias Encefálicas/patologia , Astrocitoma/patologia , Glioblastoma/patologia , Transformação Celular Neoplásica/patologia
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