• assessment
• glioblastoma
• molecular mechanism
• signaling pathway
• therapy

• Glioblastoma/genetics
• Glioblastoma/therapy
• Glioblastoma/pathology
• Humans
• Brain Neoplasms/genetics
• Brain Neoplasms/therapy
• Brain Neoplasms/pathology
• Tumor Microenvironment/genetics
• Prognosis
• Immunotherapy/methods
• Molecular Targeted Therapy/methods
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genetic Therapy/methods
• Signal Transduction/genetics
• Precision Medicine/methods
• Biomarkers, Tumor/genetics

• bioinformatics analysis
• biomarker
• cancer stem cells
• gene expression profiles
• glioblastoma

• Humans
• Glioblastoma/genetics
• Glioblastoma/pathology
• Glioblastoma/metabolism
• Glioblastoma/mortality
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Computational Biology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Brain Neoplasms/genetics
• Brain Neoplasms/pathology
• Brain Neoplasms/metabolism
• Brain Neoplasms/mortality
• Gene Expression Regulation, Neoplastic
• Secretome/metabolism
• Gene Expression Profiling
• Signal Transduction
• Prognosis
• Gene Regulatory Networks
• Protein Interaction Maps
• Tumor Microenvironment

• 57665 Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences

• PI3K
• cancer
• curcumin
• glioblastoma

• 4E-BP1
• GBM
• S6K
• mTOR
• mTORC1
• mTORC2

• Humans
• Glioblastoma/metabolism
• Intercellular Signaling Peptides and Proteins/therapeutic use
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Mechanistic Target of Rapamycin Complex 2/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction
• Sirolimus/pharmacology
• TOR Serine-Threonine Kinases/metabolism
• Neoplastic Stem Cells/metabolism

• NA Advanced Research Foundation

• Apoptosis
• Autophagy
• Glioma
• Indole steroid
• Mitochondria

• Animals
• Rats
• Hydroxysteroids/pharmacology
• Apoptosis
• Glioma/metabolism
• Indoles/pharmacology
• Autophagy
• Tryptamines/pharmacology
• Cell Line, Tumor

• cell biology
• diseases

• Humans
• Animals
• Mice
• Antioxidants
• Kelch-Like ECH-Associated Protein 1/genetics
• NF-E2-Related Factor 2/genetics
• Glioblastoma/genetics
• Mice, Nude
• Reactive Oxygen Species
• Endoplasmic Reticulum Stress
• Ubiquitin-Protein Ligases

• National Natural Science Foundation of China (National Science Foundation of China)
• Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)

• autophagy
• autophagy-related proteins
• glioblastomas
• gliomas
• prognosis
• treatment

• autophagy
• glioblastoma
• hypoxia
• niche
• stem cell
• therapy

• 81972359 National Natural Science Foundation of China

• Autophagy
• Cell death
• Glioblastoma
• Invasiveness
• MicroRNAs
• miR-targeting therapy

• GBM
• GBM cancer stem cell
• GSC
• STAT3
• autophagy
• glioblastoma
• glioma

• R01 CA281977 NCI NIH HHS
• R01 GM138393 NIGMS NIH HHS
• R21 CA233028 NCI NIH HHS

• BRD2
• BRD4
• GBM
• autophagy
• differentiation
• epigenome

• IG-23010 AIRC
• not applicable Fund for Departmental Research, University of Molise

• PRNP
• autophagia
• cellular prion protein (PrPC)
• prion protein

• Humans
• Prion Proteins
• Prions/metabolism
• Glioma/genetics
• Autophagy
• Carcinogenesis/genetics
• Cell Transformation, Neoplastic/genetics
• PrPC Proteins/metabolism
• Tumor Microenvironment

• DRP1 lysosomes
• Fis1
• Parkin
• Pink1
• cytofluorimetry
• mTOR
• mitochondrial fission
• rapamycin

• Humans
• Glioblastoma/metabolism
• Prion Proteins/metabolism
• TOR Serine-Threonine Kinases/metabolism
• Autophagy
• Mitochondria/metabolism

• Glioblastoma
• Stem cell
• mTOR
• mTORC1
• mTORC2

• Autophagy
• Glioblastoma
• Therapy
• Tumorigenesis

• Humans
• Glioblastoma/drug therapy
• Glioblastoma/metabolism
• Brain Neoplasms/drug therapy
• Brain Neoplasms/metabolism
• Autophagy

• N-heterocyclic carbene
• autophagy
• cancer stem cells
• glioblastoma
• platinum
• polyethylenimine
• polymer–drug conjugate

Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies.

Glioblastoma is a highly aggressive brain tumor. A big effort is required to find novel molecules which can cross the blood–brain barrier and efficiently kill these tumor cells. In this perspective, trehalose (α-glucopyranosyl‐[1→1]‐α‐d‐glucopyranoside), found in various dietary sources and used as a safe nutrient supplement, attracted our attention for its pleiotropic effects against tumor cells.

Human glioblastoma cell lines U373-MG and T98G were exposed to trehalose and analyzed at different time points. Cell proliferation was evaluated at medium term, and clonogenic capacity and cell morphology were evaluated at long term. Western blot was used to evaluate biochemical markers of autophagy (also measured in cells co-treated with EIPA or chloroquine), and mTOR, AMPK and ERK 1/2 signalling. Macropinocytosis was evaluated morphologically by bright-field microscopy; in cells loaded with the fluorescein-conjugated fluid-phase tracer dextran, macropinocytic vacuoles were also visualized by fluorescence microscopy, and the extent of macropinocytosis was quantified by flow cytometry.

The long-term effect of trehalose on U373-MG and T98G cell lines was impressive, as indicated by a dramatic reduction in clonogenic efficiency. Mechanistically, trehalose proved to be an efficient autophagy inducer in macropinocytosis-deficient T98G cells and an efficient inducer of macropinocytosis and eventual cell death by methuosis in U373-MG glioblastoma cells, proved to be poorly responsive to induction of autophagy. These two processes appeared to act in a mutually exclusive manner; indeed, co-treatment of U373-MG cells with the macropinocytosis inhibitor, EIPA, significantly increased the autophagic response. mTOR activation and AMPK inhibition occurred in a similar way in the two trehalose-treated cell lines. Interestingly, ERK 1/2 was activated only in macropinocytosis-proficient U373-MG cells harbouring loss-of-function mutations in the negative RAS regulator, NF1, suggesting a key role of RAS signalling.

Our results indicate that trehalose is worthy of further study as a candidate molecule for glioblastoma therapy, due to its capacity to induce a sustained autophagic response, ultimately leading to loss of clonogenic potential, and more interestingly, to force macropinocytosis, eventually leading to cell death by methuosis, particularly in tumor cells with RAS hyperactivity. As a further anticancer strategy, stimulation of macropinocytosis may be exploited to increase intracellular delivery of anticancer drugs.

• Autophagy
• ERK 1/2
• Glioblastoma cells
• Macropinocytosis
• Methuosis
• NF1
• Trehalose

• Atg14
• Beclin1
• Caspase-3
• LC3-I/LC3-II; Prom1/CD133
• MRT68921
• RAD001 (Everolimus)
• Sequestome/p62; autophagy flux; mTORC1/2
• apoptosis
• cathepsin D
• tuberin/TSC2

Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.

• brain tumors
• curcumin
• epigallocatechin gallate
• glioblastoma
• glioma tumors
• natural compounds
• resveratrol

• Blood-Brain Barrier/pathology
• Brain/pathology
• Brain Neoplasms/pathology
• Cell Line, Tumor
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• Humans
• Temozolomide/therapeutic use

• CUP: B84I18000540002 Tecnopolo per la medicina di precisione (TecnoMed Puglia)-Regione Puglia: DGR no. 2117 del 21/11/2018
• CUP: B83B17000010001. Tecnopolo di Nanotecnologia e Fotonica per la medicina di precisione (TECNOMED)- FISR/MIUR-CNR: delibera CIPE no. 3449 del 7-08-2017,

The accumulation of alpha-synuclein (α-syn) is considered a pathological hallmark of the neurodegenerative disorders known as synucleinopathies. The clearance of α-syn depends on autophagy activity, which is inhibited by the mechanistic target of rapamycin (mTOR). Thus, it is likely that α-syn accumulation may occur whenever mTOR is overactive and autophagy is suppressed. In fact, the lack of effective autophagy increases the amount of α-syn and may produce protein aggregation. Therefore, in the present study, we questioned whether cells from glioblastoma multiforme (GBM), a lethal brain neoplasm, wherein mTOR is upregulated and autophagy is suppressed, may overexpress α-syn. In fact, a large quantity of α-syn is measured in GBM cells compared with astrocytes, which includes proteinase K-resistant α-syn. Rapamycin, while inhibiting mTOR activity, significantly reduces the amount of α-syn and allocates α-syn within autophagy-like vacuoles.

Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.

• autophagy vacuoles
• cell-clearing systems
• glioblastoma multiforme
• mechanistic target of rapamycin
• qRT-PCR
• siRNA
• synucleins
• transmission electron microscopy

• Cancer stem cells
• ER stress
• ER-phagy
• FAM134B
• Sec23a

• Animals
• Autophagy
• Cell Line, Tumor
• Melanoma/pathology
• Mice
• Mice, Nude
• Neoplastic Stem Cells/metabolism
• Skin Neoplasms/metabolism
• Melanoma, Cutaneous Malignant

• National Natural Science Foundation of China

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Recent studies have shown that cancer processes are involved under normoxic conditions. These findings completely change the way of approaching the study of the cancer process. In this review, we focus on the fact that, under normoxic conditions, the overstimulation of the WNT/β-catenin pathway leads to modifications in the tumor micro-environment and the activation of the Warburg effect, i.e., aerobic glycolysis, autophagy and glutaminolysis, which in turn participate in tumor growth.

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

• HIF-1α
• VEGF
• WNT/β-catenin pathway
• Warburg effect
• aerobic glycolysis
• angiogenesis
• autophagy
• cancer
• glutaminolysis
• lactate
• metabolic reprogramming
• normoxia

• Differentiation
• Glioblastoma
• Glioma stem cells
• SOX transcription factors
• Stemness

DLK1 is a maternally imprinted, paternally expressed gene coding for the transmembrane protein Delta-like homologue 1 (DLK1), a non-canonical NOTCH ligand with well-described roles during development, and tumor-supportive functions in several aggressive cancer forms. Here, we review the many functions of DLK1 as a regulator of stem cell pools and tissue differentiation in tissues such as brain, muscle, and liver. Furthermore, we review recent evidence supporting roles for DLK1 in the maintenance of aggressive stem cell characteristics of tumor cells, specifically focusing on central nervous system tumors, neuroblastoma, and hepatocellular carcinoma. We discuss NOTCH -dependent as well as NOTCH-independent functions of DLK1, and focus particularly on the complex pattern of DLK1 expression and cleavage that is finely regulated from a spatial and temporal perspective. Progress in recent years suggest differential functions of extracellular, soluble DLK1 as a paracrine stem cell niche-secreted factor, and has revealed a role for the intracellular domain of DLK1 in cell signaling and tumor stemness. A better understanding of DLK1 regulation and signaling may enable therapeutic targeting of cancer stemness by interfering with DLK1 release and/or intracellular signaling.

• DLK1
• angiogenesis
• cancer
• glioblastoma
• stem cell
• stemness
• tissue differentiation
• tumor heterogeneity
• tumor immune infiltrate
• tumor microenvironment

The WNT (Wingless/Integrated) signaling pathway is implicated in various stages of glioblastoma, which is an aggressive brain tumor for which therapeutic options are limited. WNT has been recognized as a hallmark of therapeutic challenge due to its context-dependent role and critical function in healthy tissue homeostasis. In this review, we deeply scrutinize the WNT signaling pathway and its involvement in the genesis of glioblastoma as well as its acquired therapy resistance. We also provide an analysis of the WNT pathway in terms of its therapeutic importance in addition to an overview of the current targeted therapies under clinical investigation.

• WNT
• beta-catenin
• drug
• glioblastoma
• resistance
• therapeutic

Therapeutic resistance and infiltrative capacities justify the aggressiveness of glioblastoma. This is due to cellular heterogeneity, especially the presence of stemness-related cells, i.e. Cancer Stem Cells (CSC). Previous studies focused on autophagy and its role in CSCs maintenance; these studies gave conflicting results as they reported either sustaining or disruptive effects. In the present work, we silenced two autophagy related genes -either Beclin1 or ATG5- by shRNA and we explored the ensuing consequences on CSCs markers’ expression and functionalities. Our results showed that the down regulation of autophagy led to enhancement in expression of CSCs markers, while proliferation and clonogenicity were boosted. Temozolomide (TMZ) treatment failed to induce apoptotic death in shBeclin1-transfected cells, contrary to control. We optimized the cellular subset analysis with the use of Sedimentation Field Flow Fractionation, a biological event monitoring- and cell sorting-dedicated technique. Fractograms of both shBeclin1 and shATG5 cells exhibited a shift of elution peak as compared with control cells, showing cellular dispersion and intrinsic sub-fraction modifications. The classical stemness fraction (i.e. F3) highlighted data obtained with the overall cellular population, exhibiting enhancement of stemness markers and escape from dormancy. Our results contributed to illustrate CSCs polydispersity and to show how these cells develop capacity to bypass autophagy inhibition, thanks to their acute adaptability and plasticity.

• SdFFF cell sorting
• autophagy
• cancer stem cells
• glioblastoma
• plasticity

• Cancer
• Chemotherapy
• Interconversion
• Plasticity
• Stem cells
• Stemness

• SC1 GM121287 NIGMS NIH HHS
• SC3 GM122655 NIGMS NIH HHS

Glioblastoma (GBM) is the most common and aggressive brain tumor with an incidence rate of nearly 3.19/100,000. Current therapeutic options fall short in improving the survival of patients with GBM. Various genetic and microenvironmental factors contribute to GBM progression and resistance to therapy. The development of gene therapies using self-replicating oncolytic viruses can advance GBM treatment. Due to GBM heterogeneity, oncolytic viruses have been genetically modified to improve the antiglioma effect in vitro and in vivo. Oncolytic viruses can activate autophagy signaling in GBM upon tumoral infection. Autophagy can be cytoprotective, whereby the GBM cells catabolize damaged organelles to accommodate to virus-induced stress, or cytotoxic, whereby it leads to the destruction of GBM cells. Understanding the molecular mechanisms that control oncolytic virus-induced autophagic signaling in GBM can fuel further development of novel and more effective genetic vectors.

Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of the autophagosome and lysosomes. Recent reports have demonstrated that various chemotherapeutic agents and viral gene therapeutic vehicles provide therapeutic advantages for patients with glioblastoma as monotherapy or in combination with standards of care. Despite nonstop efforts to develop effective antiglioma therapeutics, tumor-induced autophagy in some studies manifests tumor resistance and glioma progression. Here, we explore the functional link between autophagy regulation mediated by oncolytic viruses and discuss how intracellular interactions control autophagic signaling in glioblastoma. Autophagy induced by oncolytic viruses plays a dual role in cell death and survival. On the one hand, autophagy stimulation has mostly led to an increase in cytotoxicity mediated by the oncolytic virus, but, on the other hand, autophagy is also activated as a cell defense mechanism against intracellular pathogens and modulates antiviral activity through the induction of ER stress and unfolded protein response (UPR) signaling. Despite the fact that the moment of switch between autophagic prosurvival and prodeath modes remains to be known, in the context of oncolytic virotherapy, cytotoxic autophagy is a crucial mechanism of cancer cell death.

• apoptosis
• autophagy
• oncolytic virus

• autophagy
• cell invasion
• drug resistance
• glioblastoma
• intratumoral heterogeneity (ITH)
• pro-tumoral

• autophagy
• glioblastoma multiforme
• treatment

• Autophagy/genetics
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Glioblastoma/genetics
• Glioblastoma/metabolism
• Humans
• Signal Transduction/genetics

• 2021R1A2C1003561, 2019R1I1A3A010 National Research Foundation of Korea

• Clinical outcomes
• Glioblastoma
• Immunohistochemistry markers
• Prognostic factors
• Stupp protocol

Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.

• AMBRA1
• DRP1
• FIS1
• OPA1
• PARKIN
• PINK1
• ULK1
• VPS34
• autophagy
• mitochondria

Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson’s disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.

• CMA
• LAMP2
• glioblastoma
• neurodegenerative diseases
• physiological aging

• DLK1
• Glioma
• HIF-2a
• Hypoxia
• Stem cell niche
• Tumor-associated astrocytes

• Animals
• Astrocytes/metabolism
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Biomarkers, Tumor
• Calcium-Binding Proteins/genetics
• Calcium-Binding Proteins/metabolism
• Cell Proliferation
• Cell Survival/genetics
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Glioma/metabolism
• Glioma/pathology
• Hypoxia
• Mice
• Mice, Knockout
• Tumor Burden
• Tumor Microenvironment

• anti-cancer effects
• autophagy
• curcuma longa
• glioblastoma stem-like cells
• natural polyphenols
• neuroprotection

• Autophagy/drug effects
• Cell Differentiation/drug effects
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Curcumin/pharmacology
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• Humans
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology
• Neoplastic Stem Cells/drug effects
• Signal Transduction/drug effects

• Ricerca Corrente 2020 Ministero della Salute

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor. Emerging evidence indicate the multi-faceted role of extracellular vesicles (EVs) in GBM growth and proliferation. In fact, GBM-derived EVs can alter the phenotype of GBM-associated parenchymal cells; thus, promoting tumor growth, angiogenesis, and immune evasion. Remarkably, among several pathways that are frequently deregulated in GBM, mammalian Target of Rapamycin (mTOR) up-regulation, and subsequent autophagy (ATG) depression are considered hallmarks of GBM. In fact, mTOR-dependent ATG inhibition strongly correlates with the presence of EVs, which in turn promotes glioblastoma cancer stem cells (GSCs) self-renewal, proliferation, and infiltration. ATG and exosome release are reciprocally regulated. In detail, a failure in ATG enhances exosomal release. Therefore, strategies aimed at targeting on mTOR-dependent extracellular vesicles could be a promising approach for GBM prevention and treatment.

Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.

• GSC niche
• cell-to-cell communication
• exosomes
• extracellular vesicles
• glioma cancer stem cells
• tumor microenvironment

In glioblastoma (GBM) cells, an impairment of mitochondrial activity along with autophagy suppression occurs. Autophagy suppression in GBM promotes stemness, invasion, and poor prognosis. The autophagy deficit seems to be due, at least in part, to an abnormal up-regulation of the mammalian target of rapamycin (mTOR), which may be counteracted by pharmacological mTORC1 inhibition. Since autophagy activation is tightly bound to increased mitochondriogenesis, a defect in the synthesis of novel mitochondria is expected to occur in GBM cells. In an effort to measure a baseline deficit in mitochondria and promote mitochondriogenesis, the present study used two different GBM cell lines, both featuring mTOR hyperactivity. mTORC1 inhibition increases the expression of genes and proteins related to autophagy, mitophagy, and mitochondriogenesis. Autophagy activation was counted by RT-PCR of autophagy genes, LC3- immune-fluorescent puncta and immune-gold, as well as specific mitophagy-dependent BNIP3 stoichiometric increase in situ, within mitochondria. The activation of autophagy-related molecules and organelles after rapamycin exposure occurs concomitantly with progression of autophagosomes towards lysosomes. Remarkably, mitochondrial biogenesis and plasticity (increased mitochondrial number, integrity, and density as well as decreased mitochondrial area) was long- lasting for weeks following rapamycin withdrawal.

• NRF2
• PGC1
• autophagy
• lysosomes
• mitochondrial DNA
• mitochondrial biogenesis
• mitochondrial constitutive genes
• mitophagy
• rapamycin

• Gene Expression Regulation, Neoplastic
• Glioblastoma/genetics
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Humans
• Mitochondria/genetics
• Mitochondria/metabolism
• Mitochondria/pathology
• Mitophagy
• Organelle Biogenesis
• Reactive Oxygen Species/metabolism
• TOR Serine-Threonine Kinases/genetics
• TOR Serine-Threonine Kinases/metabolism
• Tumor Cells, Cultured

• Autophagy
• COX-2
• COX-2 inhibitor
• Extracellular vesicles
• Glioblastoma
• Glioma stem cells
• Inflammation
• NS398
• T98G
• U87MG

Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABA_A receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.

• GABA
• autophagy
• dopamine
• glutamate
• neurodevelopment
• proteasome
• seizures

Glioblastoma is a solid, infiltrating, and the most frequent highly malignant primary brain tumor. Our aim was to find the correlation between sex, age, preoperative Karnofsky performance status (KPS), presenting with seizures, and extent of resection (EOR) with overall survival (OS), progression-free survival (PFS), and postoperative KPS, along with the prognostic value of IDH1, MGMT, ATRX, EGFR, and TP53 genes mutations and of Ki67 through the analysis of a single-operator series in order to avoid the biases of a multi-operator series, such as the lack of homogeneity in surgical and adjuvant nonsurgical treatments. A randomized retrospective analysis of 122 patients treated by a single first operator at Sapienza University of Rome was carried out. After surgery, patients followed standard Stupp protocol treatment. Exclusion criteria were: (1) patients with primary brainstem and spinal cord gliomas and (2) patients who underwent partial resections (resection < 90%) or a biopsy exclusively for diagnostic purposes. Statistical analysis with a simultaneous regression model was carried out through the use of SPSS 25^® (IBM). Results showed statistically significant survival increase in four groups: (1) patients treated with gross total resection (GTR) (p < 0.030); (2) patients with mutation of IDH1 (p < 0.0161); (3) patients with methylated MGMT promoter (p < 0.005); (4) patients without EGFR amplification or EGFRvIII mutation (p < 0.035). Higher but not statistically significant survival rates were also observed in: patients <75 years, patients presenting with seizures at diagnosis, patients affected by lesions in noneloquent areas, as well as in patients with ATRX gene mutation and Ki-67 < 10%.

• ATRX
• EGFR
• Epilepsy
• GTR
• Glioblastoma multiforme
• IDH1
• KPS
• Ki67
• MGMT
• Neurosurgery
• Oncology
• STR
• TP53