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1.
Life Sci ; 345: 122613, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38582393

RESUMO

Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor type, with a discouragingly low survival rate and few effective treatments. An important function of the EGFR signalling pathway in the development of GBM is to affect tumor proliferation, persistence, and treatment resistance. Advances in molecular biology in the last several years have shown how important ncRNAs are for controlling a wide range of biological activities, including cancer progression and development. NcRNAs have become important post-transcriptional regulators of gene expression, and they may affect the EGFR pathway by either directly targeting EGFR or by modifying important transcription factors and downstream signalling molecules. The EGFR pathway is aberrantly activated in response to the dysregulation of certain ncRNAs, which has been linked to GBM carcinogenesis, treatment resistance, and unfavourable patient outcomes. We review the literature on miRNAs, circRNAs and lncRNAs that are implicated in the regulation of EGFR signalling in GBM, discussing their mechanisms of action, interactions with the signalling pathway, and implications for GBM therapy. Furthermore, we explore the potential of ncRNA-based strategies to overcome resistance to EGFR-targeted therapies, including the use of ncRNA mimics or inhibitors to modulate the activity of key regulators within the pathway.


Assuntos
Neoplasias Encefálicas , Glioblastoma , MicroRNAs , Humanos , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Transdução de Sinais , MicroRNAs/metabolismo , RNA não Traduzido/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo
2.
Sci Rep ; 14(1): 8570, 2024 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-38609422

RESUMO

Glioblastoma is one of the most common and aggressive brain tumors and has seen few improvements in patient outcomes. Inter-tumor heterogeneity between tumors of different patients as well as intra-tumor heterogeneity of cells within the same tumor challenge the development of effective drugs. MiRNAs play an essential role throughout the developing brain and regulate many key genes involved in oncogenesis, yet their role in driving many of the processes underlying tumor heterogeneity remains unclear. In this study, we highlight miRNAs from the Dlk1-Dio3 and miR-224/452 clusters which may be expressed cell autonomously and have expression that is associated with cell state genes in glioblastoma, most prominently in neural progenitor-like and mesenchymal-like states respectively. These findings implicate these miRNA clusters as potential regulators of glioblastoma intra-tumoral heterogeneity and may serve as valuable biomarkers for cell state identification.


Assuntos
Neoplasias Encefálicas , Glioblastoma , MicroRNAs , Humanos , Encéfalo , Neoplasias Encefálicas/genética , Carcinogênese , Glioblastoma/genética , MicroRNAs/genética
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 49(1): 58-67, 2024 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38615167

RESUMO

OBJECTIVES: Glioblastoma (GBM) and brain metastases (BMs) are the two most common malignant brain tumors in adults. Magnetic resonance imaging (MRI) is a commonly used method for screening and evaluating the prognosis of brain tumors, but the specificity and sensitivity of conventional MRI sequences in differential diagnosis of GBM and BMs are limited. In recent years, deep neural network has shown great potential in the realization of diagnostic classification and the establishment of clinical decision support system. This study aims to apply the radiomics features extracted by deep learning techniques to explore the feasibility of accurate preoperative classification for newly diagnosed GBM and solitary brain metastases (SBMs), and to further explore the impact of multimodality data fusion on classification tasks. METHODS: Standard protocol cranial MRI sequence data from 135 newly diagnosed GBM patients and 73 patients with SBMs confirmed by histopathologic or clinical diagnosis were retrospectively analyzed. First, structural T1-weight, T1C-weight, and T2-weight were selected as 3 inputs to the entire model, regions of interest (ROIs) were manually delineated on the registered three modal MR images, and multimodality radiomics features were obtained, dimensions were reduced using a random forest (RF)-based feature selection method, and the importance of each feature was further analyzed. Secondly, we used the method of contrast disentangled to find the shared features and complementary features between different modal features. Finally, the response of each sample to GBM and SBMs was predicted by fusing 2 features from different modalities. RESULTS: The radiomics features using machine learning and the multi-modal fusion method had a good discriminatory ability for GBM and SBMs. Furthermore, compared with single-modal data, the multimodal fusion models using machine learning algorithms such as support vector machine (SVM), Logistic regression, RF, adaptive boosting (AdaBoost), and gradient boosting decision tree (GBDT) achieved significant improvements, with area under the curve (AUC) values of 0.974, 0.978, 0.943, 0.938, and 0.947, respectively; our comparative disentangled multi-modal MR fusion method performs well, and the results of AUC, accuracy (ACC), sensitivity (SEN) and specificity(SPE) in the test set were 0.985, 0.984, 0.900, and 0.990, respectively. Compared with other multi-modal fusion methods, AUC, ACC, and SEN in this study all achieved the best performance. In the ablation experiment to verify the effects of each module component in this study, AUC, ACC, and SEN increased by 1.6%, 10.9% and 15.0%, respectively after 3 loss functions were used simultaneously. CONCLUSIONS: A deep learning-based contrast disentangled multi-modal MR radiomics feature fusion technique helps to improve GBM and SBMs classification accuracy.


Assuntos
Neoplasias Encefálicas , Aprendizado Profundo , Glioblastoma , Adulto , Humanos , Glioblastoma/diagnóstico por imagem , Estudos Retrospectivos , Algoritmos , Neoplasias Encefálicas/diagnóstico por imagem
4.
Neurosurg Rev ; 47(1): 159, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38625588

RESUMO

We aim to investigate the efficacy and safety of laser interstitial thermal therapy (LITT) in treating recurrent glioblastomas (rGBMs). A comprehensive search was conducted in four databases to identify studies published between January 2001 and June 2022 that reported prognosis information of rGBM patients treated with LITT as the primary therapy. The primary outcomes of interest were progression-free survival (PFS) and overall survival (OS) at 6 and 12 months after LITT intervention. Adverse events and complications were also evaluated. Eight eligible non-comparative studies comprising 128 patients were included in the analysis. Seven studies involving 120 patients provided data for the analysis of PFS. The pooled PFS rate at 6 months after LITT was 25% (95% CI 15-37%, I2 = 53%), and at 12 months, it was 9% (95% CI 4-15%, I2 = 24%). OS analysis was performed on 54 patients from six studies, with an OS rate of 92% (95% CI 84-100%, I2 = 0%) at 6 months and 42% (95% CI 13-73%, I2 = 67%) at 12 months after LITT. LITT demonstrates a favorable safety profile with low complication rates and promising tumor control and overall survival rates in patients with rGBMs. Tumor volume and performance status are important factors that may influence the effectiveness of LITT in selected patients. Additionally, the combination of LITT with immune-based therapy holds promise. Further well-designed clinical trials are needed to expand the application of LITT in glioma treatment.


Assuntos
Glioblastoma , Glioma , Humanos , Glioblastoma/terapia , Bases de Dados Factuais , Intervalo Livre de Progressão , Lasers
5.
J Immunother Cancer ; 12(4)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38599661

RESUMO

BACKGROUND: Glioblastoma (GBM), a highly immunosuppressive and often fatal primary brain tumor, lacks effective treatment options. GBMs contain a subpopulation of GBM stem-like cells (GSCs) that play a central role in tumor initiation, progression, and treatment resistance. Oncolytic viruses, especially oncolytic herpes simplex virus (oHSV), replicate selectively in cancer cells and trigger antitumor immunity-a phenomenon termed the "in situ vaccine" effect. Although talimogene laherparepvec (T-VEC), an oHSV armed with granulocyte macrophage-colony stimulating factor (GM-CSF), is Food and Drug Administration (FDA)-approved for melanoma, its use in patients with GBM has not been reported. Interleukin 2 (IL-2) is another established immunotherapy that stimulates T cell growth and orchestrates antitumor responses. IL-2 is FDA-approved for melanoma and renal cell carcinoma but has not been widely evaluated in GBM, and IL-2 treatment is limited by its short half-life, minimal tumor accumulation, and significant systemic toxicity. We hypothesize that local intratumoral expression of IL-2 by an oHSV would avoid the systemic IL-2-related therapeutic drawbacks while simultaneously producing beneficial antitumor immunity. METHODS: We developed G47Δ-mIL2 (an oHSV expressing IL-2) using the flip-flop HSV BAC system to deliver IL-2 locally within the tumor microenvironment (TME). We then tested its efficacy in orthotopic mouse GBM models (005 GSC, CT-2A, and GL261) and evaluated immune profiles in the treated tumors and spleens by flow cytometry and immunohistochemistry. RESULTS: G47Δ-mIL2 significantly prolonged median survival without any observable systemic IL-2-related toxicity in the 005 and CT-2A models but not in the GL261 model due to the non-permissive nature of GL261 cells to HSV infection. The therapeutic activity of G47Δ-mIL2 in the 005 GBM model was associated with increased intratumoral infiltration of CD8+ T cells, critically dependent on the release of IL-2 within the TME, and CD4+ T cells as their depletion completely abrogated therapeutic efficacy. The use of anti-PD-1 immune checkpoint blockade did not improve the therapeutic outcome of G47Δ-mIL2. CONCLUSIONS: Our findings illustrate that G47Δ-mIL2 is efficacious, stimulates antitumor immunity against orthotopic GBM, and may also target GSC. OHSV expressing IL-2 may represent an agent that merits further exploration in patients with GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Herpes Simples , Melanoma , Terapia Viral Oncolítica , Estados Unidos , Animais , Camundongos , Humanos , Glioblastoma/patologia , Melanoma/terapia , Herpesvirus Humano 2 , Linfócitos T CD8-Positivos , Interleucina-2/uso terapêutico , Neoplasias Encefálicas/patologia , Microambiente Tumoral
6.
Sci Rep ; 14(1): 8738, 2024 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627421

RESUMO

Brain tumor glioblastoma is a disease that is caused for a child who has abnormal cells in the brain, which is found using MRI "Magnetic Resonance Imaging" brain image using a powerful magnetic field, radio waves, and a computer to produce detailed images of the body's internal structures it is a standard diagnostic tool for a wide range of medical conditions, from detecting brain and spinal cord injuries to identifying tumors and also in evaluating joint problems. This is treatable, and by enabling the factor for happening, the factor for dissolving the dead tissues. If the brain tumor glioblastoma is untreated, the child will go to death; to avoid this, the child has to treat the brain problem using the scan of MRI images. Using the neural network, brain-related difficulties have to be resolved. It is identified to make the diagnosis of glioblastoma. This research deals with the techniques of max rationalizing and min rationalizing images, and the method of boosted division time attribute extraction has been involved in diagnosing glioblastoma. The process of maximum and min rationalization is used to recognize the Brain tumor glioblastoma in the brain images for treatment efficiency. The image segment is created for image recognition. The method of boosted division time attribute extraction is used in image recognition with the help of MRI for image extraction. The proposed boosted division time attribute extraction method helps to recognize the fetal images and find Brain tumor glioblastoma with feasible accuracy using image rationalization against the brain tumor glioblastoma diagnosis. In addition, 45% of adults are affected by the tumor, 40% of children and 5% are in death situations. To reduce this ratio, in this study, the Brain tumor glioblastoma is identified and segmented to recognize the fetal images and find the Brain tumor glioblastoma diagnosis. Then the tumor grades were analyzed using the efficient method for the imaging MRI with the diagnosis result of partially high. The accuracy of the proposed TAE-PIS system is 98.12% which is higher when compared to other methods like Genetic algorithm, Convolution neural network, fuzzy-based minimum and maximum neural network and kernel-based support vector machine respectively. Experimental results show that the proposed method archives rate of 98.12% accuracy with low response time and compared with the Genetic algorithm (GA), Convolutional Neural Network (CNN), fuzzy-based minimum and maximum neural network (Fuzzy min-max NN), and kernel-based support vector machine. Specifically, the proposed method achieves a substantial improvement of 80.82%, 82.13%, 85.61%, and 87.03% compared to GA, CNN, Fuzzy min-max NN, and kernel-based support vector machine, respectively.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Criança , Humanos , Glioblastoma/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Encefálicas/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Algoritmos
8.
CNS Neurosci Ther ; 30(4): e14698, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38600891

RESUMO

AIMS: To investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair-related genes and the development of chemoresistance in gliomas. METHODS: We conducted a comprehensive analysis of deep-targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I-TASSER for homology modeling. We elucidated the functional changes induced by high-frequency site mutations in these genes and investigated their impact on glioma progression. RESULTS: The analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis. CONCLUSION: The ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.


Assuntos
Proteínas de Ligação a DNA , Glioblastoma , Fatores de Transcrição , Humanos , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Mutação/genética , Proteínas Nucleares/genética , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Fatores de Transcrição/genética
9.
Cancer Immunol Immunother ; 73(6): 98, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38619641

RESUMO

CAR-T-cell therapy has shown promise in treating hematological malignancies but faces challenges in treating solid tumors due to impaired T-cell function in the tumor microenvironment. To provide optimal T-cell activation, we developed a B7 homolog 3 protein (B7H3)-targeting CAR construct consisting of three activation signals: CD3ζ (signal 1), 41BB (signal 2), and the interleukin 7 receptor alpha (IL7Rα) cytoplasmic domain (signal 3). We generated B7H3 CAR-T cells with different lengths of the IL7Rα cytoplasmic domain, including the full length (IL7R-L), intermediate length (IL7R-M), and short length (IL7R-S) domains, and evaluated their functionality in vitro and in vivo. All the B7H3-IL7Rα CAR-T cells exhibited a less differentiated phenotype and effectively eliminated B7H3-positive glioblastoma in vitro. Superiority was found in B7H3 CAR-T cells contained the short length of the IL7Rα cytoplasmic domain. Integration of the IL7R-S cytoplasmic domain maintained pSTAT5 activation and increased T-cell proliferation while reducing activation-induced cell death. Moreover, RNA-sequencing analysis of B7H3-IL7R-S CAR-T cells after coculture with a glioblastoma cell line revealed downregulation of proapoptotic genes and upregulation of genes associated with T-cell proliferation compared with those in 2nd generation B7H3 CAR-T cells. In animal models, compared with conventional CAR-T cells, B7H3-IL7R-S CAR-T cells suppressed tumor growth and prolonged overall survival. Our study demonstrated the therapeutic potential of IL7Rα-incorporating CAR-T cells for glioblastoma treatment, suggesting a promising strategy for augmenting the effectiveness of CAR-T cell therapy.


Assuntos
Glioblastoma , Receptores de Antígenos Quiméricos , Animais , Glioblastoma/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Interleucina-7/genética , Transdução de Sinais , Linfócitos T , Microambiente Tumoral , Humanos
10.
Nat Commun ; 15(1): 3226, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622132

RESUMO

The tumor microenvironment plays a crucial role in determining response to treatment. This involves a series of interconnected changes in the cellular landscape, spatial organization, and extracellular matrix composition. However, assessing these alterations simultaneously is challenging from a spatial perspective, due to the limitations of current high-dimensional imaging techniques and the extent of intratumoral heterogeneity over large lesion areas. In this study, we introduce a spatial proteomic workflow termed Hyperplexed Immunofluorescence Imaging (HIFI) that overcomes these limitations. HIFI allows for the simultaneous analysis of > 45 markers in fragile tissue sections at high magnification, using a cost-effective high-throughput workflow. We integrate HIFI with machine learning feature detection, graph-based network analysis, and cluster-based neighborhood analysis to analyze the microenvironment response to radiation therapy in a preclinical model of glioblastoma, and compare this response to a mouse model of breast-to-brain metastasis. Here we show that glioblastomas undergo extensive spatial reorganization of immune cell populations and structural architecture in response to treatment, while brain metastases show no comparable reorganization. Our integrated spatial analyses reveal highly divergent responses to radiation therapy between brain tumor models, despite equivalent radiotherapy benefit.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Camundongos , Proteômica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Glioblastoma/patologia , Encéfalo/patologia , Imunofluorescência , Microambiente Tumoral
11.
BMC Med Genomics ; 17(1): 83, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594690

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary CNS tumor, characterized by high mortality and heterogeneity. However, the related lncRNA signatures and their target microRNA (miRNA) for GBM are still mostly unknown. Therefore, it is critical that we discover lncRNA markers in GBM and their biological activities. MATERIALS AND METHODS: GBM-related RNA-seq data were obtained from the Cancer Genome Atlas (TCGA) database. The "edger" R package was used for differently expressed lncRNAs (DELs) identification. Then, we forecasted prospective miRNAs that might bind to lncRNAs by Cytoscape software. Survival analysis of those miRNAs was examined by the starBase database, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the miRNAs' target genes was conducted by the Gene Set Enrichment Analysis (GSEA) database and R software. Moreover, the proliferative ability of unc-5 netrin receptor B antisense RNA 1 (UNC5B-AS1) cells was evaluated by Cell Counting Kit-8 (CCK-8) analysis. Mechanistically, the regulatory interaction between UNC5B-AS1 and miRNA in GBM biological processes was studied using CCK-8 analysis. RESULTS: Our results indicated that overexpression of UNC5B-AS1 has been shown to suppress GBM cell growth. Mechanistically, miR-24-3p in GBM was able to alleviate the anti-oncogenic effects of UNC5B-AS1 on cell proliferation. CONCLUSION: The discovery of the novel UNC5B-AS1-miR-24-3p network suggests possible lncRNA and miRNA roles in the development of GBM, which may have significant ramifications for the analysis of clinical prognosis and the development of GBM medications.


Assuntos
Glioblastoma , MicroRNAs , RNA Longo não Codificante , Humanos , Glioblastoma/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Estudos Prospectivos , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Receptores de Netrina/genética , Receptores de Netrina/metabolismo
12.
Oncoimmunology ; 13(1): 2338965, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590799

RESUMO

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Células Supressoras Mieloides , Humanos , Camundongos , Animais , Glioma/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Células Mieloides/patologia , Neoplasias Encefálicas/tratamento farmacológico , Microambiente Tumoral , Receptores CCR2 , Receptores CCR5/uso terapêutico
13.
Sci Rep ; 14(1): 7984, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38575630

RESUMO

The extent of surgical resection is an important prognostic factor in the treatment of patients with glioblastoma. Optical coherence tomography (OCT) imaging is one of the adjunctive methods available to achieve the maximal surgical resection. In this study, the tumor margins were visualized with the OCT image obtained from a murine glioma model. A commercialized human glioblastoma cell line (U-87) was employed to develop the orthotopic murine glioma model. A swept-source OCT (SS-OCT) system of 1300 nm was used for three-dimensional imaging. Based on the OCT intensity signal, which was obtained via accumulation of each A-scan data, an en-face optical attenuation coefficient (OAC) map was drawn. Due to the limited working distance of the focused beam, OAC values decrease with depth, and using the OAC difference in the superficial area was chosen to outline the tumor boundary, presenting a challenge in analyzing the tumor margin along the depth direction. To overcome this and enable three-dimensional tumor margin detection, we converted the en-face OAC map into an en-face difference map with x- and y-directions and computed the normalized absolute difference (NAD) at each depth to construct a volumetric NAD map, which was compared with the corresponding H&E-stained image. The proposed method successfully revealed the tumor margin along the peripheral boundaries as well as the margin depth. We believe this method can serve as a useful adjunct in glioma surgery, with further studies necessary for real-world practical applications.


Assuntos
Glioblastoma , Glioma , Humanos , Animais , Camundongos , Glioblastoma/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , NAD , Glioma/patologia , Imageamento Tridimensional
14.
Molecules ; 29(7)2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38611962

RESUMO

Phytocompounds have been evaluated for their anti-glioblastoma actions for decades, with promising results from preclinical studies but only limited translation into clinics. Indeed, by targeting multiple signaling pathways deregulated in cancer, they often show high efficacy in the in vitro studies, but their poor bioavailability, low tumor accumulation, and rapid clearance compromise their efficacy in vivo. Here, we present the new avenues in phytocompound research for the improvement of glioblastoma therapy, including the ways to enhance the response to temozolomide using phytochemicals, the current focus on phytocompound-based immunotherapy, or the use of phytocompounds as photosensitizers in photodynamic therapy. Moreover, we present new, intensively evaluated approaches, such as chemical modifications of phytochemicals or encapsulation into numerous types of nanoformulations, to improve their bioavailability and delivery to the brain. Finally, we present the clinical trials evaluating the role of phytocompounds or phytocompound-derived drugs in glioblastoma therapy and the less studied phytocompounds or plant extracts that have only recently been found to possess promising anti-glioblastoma properties. Overall, recent advancements in phytocompound research are encouraging; however, only with more 3D glioblastoma models, in vivo studies, and clinical trials it is possible to upgrade the role of phytocompounds in glioblastoma treatment to a satisfactory level.


Assuntos
Glioblastoma , Fotoquimioterapia , Humanos , Glioblastoma/tratamento farmacológico , Encéfalo , Temozolomida , Imunoterapia
15.
Int J Mol Sci ; 25(7)2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38612480

RESUMO

The aim of this study was to investigate gene expression alterations associated with overall survival (OS) in glioblastoma (GBM). Using the Nanostring nCounter platform, we identified four genes (COL1A2, IGFBP3, NGFR, and WIF1) that achieved statistical significance when comparing GBM with non-neoplastic brain tissue. The four genes were included in a multivariate Cox Proportional Hazard model, along with age, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation, to create a unique glioblastoma prognostic index (GPI). The GPI score inversely correlated with survival: patient with a high GPI had a median OS of 7.5 months (18-month OS = 9.7%) whereas patients with a low GPI had a median OS of 20.1 months (18-month OS = 54.5%; log rank p-value = 0.004). The GPI score was then validated in 188 GBM patients from The Cancer Genome Atlas (TCGA) from a national data base; similarly, patients with a high GPI had a median OS of 10.5 months (18-month OS = 12.4%) versus 16.9 months (18-month OS = 41.5%) for low GPI (log rank p-value = 0.0003). We conclude that this novel mRNA-based prognostic index could be useful in classifying GBM patients into risk groups and refine prognosis estimates to better inform treatment decisions or stratification into clinical trials.


Assuntos
Glioblastoma , Humanos , Glioblastoma/genética , Genes Reguladores , Bases de Dados Factuais , O(6)-Metilguanina-DNA Metiltransferase , Expressão Gênica
16.
Int J Mol Sci ; 25(7)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38612758

RESUMO

The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.


Assuntos
Glioblastoma , Glioma , Humanos , Proteína Supressora de Tumor p53/genética , Glioma/tratamento farmacológico , Glioma/genética , Apoptose , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-mdm2/genética
17.
Int J Mol Sci ; 25(7)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38612755

RESUMO

Glypicans are linked to various aspects of neoplastic behavior, and their therapeutic value has been proposed in different cancers. Here, we have systematically assessed the impact of GPC4 on cancer progression through functional genomics and transcriptomic analyses across a broad range of cancers. Survival analysis using TCGA cancer patient data reveals divergent effects of GPC4 expression across various cancer types, revealing elevated GPC4 expression levels to be associated with both poor and favorable prognoses in a cancer-dependent manner. Detailed investigation of the role of GPC4 in glioblastoma and non-small cell lung adenocarcinoma by genetic perturbation studies displays opposing effects on these cancers, where the knockout of GPC4 with CRISPR/Cas9 attenuated proliferation of glioblastoma and augmented proliferation of lung adenocarcinoma cells and the overexpression of GPC4 exhibited a significant and opposite effect. Further, the overexpression of GPC4 in GPC4-knocked-down glioblastoma cells restored the proliferation, indicating its mitogenic effect in this cancer type. Additionally, a survival analysis of TCGA patient data substantiated these findings, revealing an association between elevated levels of GPC4 and a poor prognosis in glioblastoma, while indicating a favorable outcome in lung carcinoma patients. Finally, through transcriptomic analysis, we attempted to assign mechanisms of action to GPC4, as we find it implicated in cell cycle control and survival core pathways. The analysis revealed upregulation of oncogenes, including FGF5, TGF-ß superfamily members, and ITGA-5 in glioblastoma, which were downregulated in lung adenocarcinoma patients. Our findings illuminate the pleiotropic effect of GPC4 in cancer, underscoring its potential as a putative prognostic biomarker and indicating its therapeutic implications in a cancer type dependent manner.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Glioblastoma , Neoplasias Pulmonares , Humanos , Glipicanas/genética , Glioblastoma/genética , Oncogenes , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética
18.
Int J Mol Sci ; 25(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38612777

RESUMO

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.


Assuntos
Glioblastoma , Glioma , Doença de Parkinson , Humanos , Glioblastoma/genética , Proteínas de Membrana/genética , Células Endoteliais , 60489 , Glioma/genética , Neuroglia , Neovascularização Patológica/genética
19.
Int J Mol Sci ; 25(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38612788

RESUMO

Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of S. cerevisiae yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors.


Assuntos
Glioblastoma , Saccharomyces cerevisiae , Humanos , Complexo de Endopeptidases do Proteassoma , Glioblastoma/tratamento farmacológico , Bortezomib/farmacologia , Células HEK293
20.
Int J Mol Sci ; 25(7)2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38612892

RESUMO

Glioblastoma (GBM) is a fatal brain tumor with limited treatment options. O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is the central molecular biomarker linked to both the response to temozolomide, the standard chemotherapy drug employed for GBM, and to patient survival. However, MGMT status is captured on tumor tissue which, given the difficulty in acquisition, limits the use of this molecular feature for treatment monitoring. MGMT protein expression levels may offer additional insights into the mechanistic understanding of MGMT but, currently, they correlate poorly to promoter methylation. The difficulty of acquiring tumor tissue for MGMT testing drives the need for non-invasive methods to predict MGMT status. Feature selection aims to identify the most informative features to build accurate and interpretable prediction models. This study explores the new application of a combined feature selection (i.e., LASSO and mRMR) and the rank-based weighting method (i.e., MGMT ProFWise) to non-invasively link MGMT promoter methylation status and serum protein expression in patients with GBM. Our method provides promising results, reducing dimensionality (by more than 95%) when employed on two large-scale proteomic datasets (7k SomaScan® panel and CPTAC) for all our analyses. The computational results indicate that the proposed approach provides 14 shared serum biomarkers that may be helpful for diagnostic, prognostic, and/or predictive operations for GBM-related processes, given further validation.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Proteômica , Temozolomida/uso terapêutico , Proteínas Sanguíneas , Neoplasias Encefálicas/genética , O(6)-Metilguanina-DNA Metiltransferase , Metilases de Modificação do DNA/genética , Proteínas Supressoras de Tumor/genética , Enzimas Reparadoras do DNA/genética
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