OBJECT:Glioblastoma multiforme(GBM)is the most common and lethal primary brain tumor in adults.It isnearly uniformly fatal,with a median survival time of approximately l year,despite modem treatment modalities.Neverth...OBJECT:Glioblastoma multiforme(GBM)is the most common and lethal primary brain tumor in adults.It isnearly uniformly fatal,with a median survival time of approximately l year,despite modem treatment modalities.Nevertheless,a range of survival times exists around this median.Efforts to understand why some patients livelonger or shorter than the average may provide insight into the biology of these neoplasms.The annexin VII(ANX7)gene is located on the human chromosome 10q21,a site long hypothesized to harbor tumor展开更多
Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the...Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure.Mechanisms underlying the development of resistance involve multiple factors,including drug efflux,DNA damage repair,glioma stem cells,and a hypoxic tumor environment,which are usually correlative and promote each other.As many potential therapeutic targets have been discovered,combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy.In recent years,nanomedicine has revolutionized cancer therapies with optimized accumulation,penetration,internalization,and controlled release.Blood-brain barrier(BBB)penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB.Moreover,different drugs for combination therapy usually process different pharmacokinetics and biodistribution,which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies.Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed.This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.展开更多
Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresist...Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.展开更多
Background Recent studies have suggested that cancer stem cells are one of the major causes for tumor recurrence due to their resistance to radiotherapy and chemotherapy. Although the highly invasive nature of gliobla...Background Recent studies have suggested that cancer stem cells are one of the major causes for tumor recurrence due to their resistance to radiotherapy and chemotherapy. Although the highly invasive nature of glioblastoma （GBM） cells is also implicated in the failure of current therapies, it is not clear how glioma stem cells （GSCs） are involved in invasiveness. Racl activity is necessary for inducing reorganization of actin cytoskeleton and cell movement. In this study, we aimed to investigate the distribution characteristics of CD133＋ cells and Racl＋ cells in GBM as well as Racl activity in CD133＋ GBM cells, and analyze the migration and invasion potential of these cells. Methods A series of 21 patients with GBM were admitted consecutively and received tumor resection in Tianjin Medical University General Hospital during the first half of the year 2011. Tissue specimens were collected both from the peripheral and the central parts for each tumor under magnetic resonance imaging （MRI） navigation guidance. Immunohistochemical staining was used to detect the CD133＋ cells and Racl＋ cells distribution in GBM specimens. Double-labeling immunofluorescence was further used to analyze CD133 and Racl co-expression and the relationship between CD133＋ cells distribution and Racl expression. Serum-free medium culture and magnetic sorting were used to isolate CD133＋ cells from U87 cell line. Racl activation assay was conducted to assess the activation of Racl in CD133＋ and CD133- U87 cells. The migration and invasive ability of CD133＋ and CD133- U87 cells were determined by cell migration and invasion assays in vitro. Student＇s t-test and one-way analysis of variance （ANOVA） test were used to determine statistical significance in this study. Results In the central parts of GBMs, CD133＋ cells were found to cluster around necrosis and occasionally cluster around the vessels under the microscope by immunohistological staining. In the peripheral parts of the tumors, CD133＋ cells were lined up along the basement membrane of the vessels and myelinated nerve fibers. Racl expression was high and diffused in the central parts of the GBMs, and the Racl＋ cells were distributed basically in accordance with CD133＋ cells both in the central and peripheral parts of GBMs. In double-labeling immunofluorescence, Racl was expressed in （83.14＋4.23）% of CD133＋ cells, and CD133 and Racl co-expressed cells were located around the vessels in GBMs. Significantly higher amounts of Racl-GTP were expressed in the CD133＋ cells （0.378±0.007）, compared to CD133- cells （0.195±0.004） （t=-27.81; P 〈0.05）. CD133＋ cells had stronger ability to migrate （74.34±2.40 vs. 38.72±2.60, t=42.71, P 〈0.005） and invade （52.00±2.28 vs. 31.26±1.82, t=30.76, P 〈0.005）, compared to their counterpart CD133- cells in transwell cell migration/invasion assay. Conclusions These data suggest that CD133＋ GBM cells highly express Racl and have greater potential to migrate and invade through activated Racl-GTP. The accordance of distribution between Racl＋ cells and CD133＋ cells in GBMs implies that Racl might be an inhibited target to prevent invasion and migration and to avoid malignant glioma recurrence展开更多
Glioblastoma multiforme （GBM） is the most common adult primary tumor of the cen- tral nervous system. The current standard of care for glioblastoma patients involves a combination of surgery, radiotherapy and chemot...Glioblastoma multiforme （GBM） is the most common adult primary tumor of the cen- tral nervous system. The current standard of care for glioblastoma patients involves a combination of surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide. Several mech- anisms underlying the inherent and acquired temozolomide resistance have been identified and con- tribute to treatment failure. Early identification of temozolomide-resistant GBM patients and improvement of the therapeutic strategies available to treat this malignancy are of uttermost impor- tance. This review initially looks at the molecular pathways underlying GBM formation and devel- opment with a particular emphasis placed on recent therapeutic advances made in the field. Our focus will next be directed toward the molecular mechanisms modulating temozolomide resistance in GBM patients and the strategies envisioned to circumvent this resistance. Finallyl we highlight the diagnostic and prognostic value of metabolomics in cancers and assess its potential usefulness in improving the current standard of care for GBM patients.展开更多
Human cytomegalovirus (HCMV) was reported in glioblastoma multiforme (GBM) over a decade ago and this finding has the potential to increase our understanding of the disease and it offers an alternative tumor-specific ...Human cytomegalovirus (HCMV) was reported in glioblastoma multiforme (GBM) over a decade ago and this finding has the potential to increase our understanding of the disease and it offers an alternative tumor-specific therapeutic target. Due of this promise, there is a fair amount of time, energy and money being directed towards understanding and utilizing this connection for eventual therapeutic purposes. Nevertheless, the association between GBM and HCMV remains controversial. Several studies have reported conflicting results, further undermining the potential clinical value of this association. In this review, the authors will discuss the latest developments on this evolving issue. Specifically, the results of the latest studies, both positive and negative, will be discussed. Furthermore, potential theories to explain discrepancies reported in the literature will be proposed. Clinical implications including potential targets for anti-HCMV therapy and the latest developments in anti-HCMV therapy will be presented. Finally, solutions to remedy this controversial issue in neuro-oncology will be offered.展开更多
The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an a...The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an anti-angiogenic therapy[an antibody against the vascular endothelial growth factor(bevacizumab;Avastin)],resulting in recurrent tumors.Several recurrent GBM tumors are commonly resistant to either TMZ,radiation or bevacizumab,which contributes to the low survival rate for GBM patients.This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance.One of these therapeutic options is a small molecule called OKlahoma Nitrone 007(OKN-007),which was discovered to inhibit the transforming growth factor β1 pathway,reduce TMZ-resistance and enhance TMZ-sensitivity.OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients.Another novel target is ELTD1(epidermal growth factor,latrophilin and seven transmembrane domain-containing protein 1;alternatively known as ADGRL4,Adhesion G protein-coupled receptor L4),which we used a monoclonal antibody against,where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model.Notch 1 is known to be associated with chemoresistance in GBM.Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway,nuclear factor-κB,the hepatocyte/scatter factor(c-MET),the epidermal growth factor receptor,and the tumor microenvironment.展开更多
Glioblastoma multiforme(GBM),a highly malignant and heterogeneous brain tumor,contains various types of tumor and non-tumor cells.Whether GBM cells can trans-differentiate into non-neural cell types,including mural ce...Glioblastoma multiforme(GBM),a highly malignant and heterogeneous brain tumor,contains various types of tumor and non-tumor cells.Whether GBM cells can trans-differentiate into non-neural cell types,including mural cells or endothelial cells(ECs),to support tumor growth and invasion remains controversial.Here we generated two genetic GBM models de novo in immunocompetent mouse brains,mimicking essential pathological and molecular features of human GBMs.Lineage-tracing and transplantation studies demonstrated that,although blood vessels in GBM brains underwent drastic remodeling,evidence of trans-differentiation of GBM cells into vascular cells was barely detected.Intriguingly,GBM cells could promiscuously express markers for mural cells during gliomagenesis.Furthermore,single-cell RNA sequencing showed that patterns of copy number variations(CNVs)of mural cells and ECs were distinct from those of GBM cells,indicating discrete origins of GBM cells and vascular components.Importantly,single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages.Rather than expansion owing to trans-differentiation,vascular cell expanded by proliferation during tumorigenesis.Therefore,cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis.Our findings advance understanding of cell lineage dynamics during gliomagenesis,and have implications for targeted treatment of GBMs.展开更多
Glioblastoma(GBM)is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking,followed by radiation therapy with concurrent and ...Glioblastoma(GBM)is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking,followed by radiation therapy with concurrent and adjuvant temozolomide treatment.The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy.Several mechanisms including inter-and intratumoral heterogeneity,the evolution of therapy-resistant clonal subpopulations,reacquisition of stemness in glioblastoma stem cells,multiple drug efflux mechanisms,the tumor-promoting microenvironment,metabolic adaptations,and enhanced repair of drug-induced DNA damage have been implicated in therapy failure.Extracellular vesicles(EVs)have emerged as crucial mediators in the maintenance and establishment of GBM.Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance.Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies.In this review,we discuss the various mechanisms of therapy resistance in GBM,highlighting the emerging role of EV-orchestrated drug resistance.Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.展开更多
Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiqu...Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of SUMOylation.We used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers.We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by nutlin-3.This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation.Using comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma progression.We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation.Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway.Its efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or exercise.Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation.Notably,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells.These results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma management.Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.展开更多
BACKGROUND Glioblastoma multiforme(GBM)is the most aggressive and prevalent primary malignant brain tumor in adults,marked by poor prognosis and high invasiveness.Traditional GBM invasion assays,such as those involvin...BACKGROUND Glioblastoma multiforme(GBM)is the most aggressive and prevalent primary malignant brain tumor in adults,marked by poor prognosis and high invasiveness.Traditional GBM invasion assays,such as those involving mouse brain xenografts,are often time-consuming and limited in efficiency.In this context,stem cell-derived neural organoids(NOs)have emerged as advanced,threedimensional,human-relevant platforms that mimic the cellular architecture and microenvironment of the human brain.These models provide novel opportunities to investigate glioblastoma stem cell invasion,a critical driver of tumor progression and therapeutic resistance.AIM To evaluate studies using stem cell-derived NOs to model glioblastoma migration/invasion,focusing on methodologies,applications and therapeutic implications.METHODS We conducted a systematic review following PRISMA guidelines,searching PubMed and Scopus for studies published between March 2019 and March 2025 that investigated NOs in the context of glioblastoma invasion/migration.After screening 377 articles based on predefined inclusion and exclusion criteria,10 original research articles were selected for analysis.Extracted data were categorized into four analytical domains:(1)Tumor model formation;(2)NO characteristics;(3)NO differentiation protocols;and(4)Invasion/migration assessment methodologies.RESULTS The included studies exhibit significant methodological heterogeneity GBM model development,particularly regarding model type,cell source and culture conditions.Most studies(70%)used suspension cell models,while 30%employed spheroids,with most research focusing on patient-derived glioblastoma stem cells.NOs were predominantly generated from human induced pluripotent stem cells using both guided and unguided differentiation protocols.Confocal fluorescence microscopy was the primary method used for assessing invasion,revealing invasion depths of up to 300μm.Organoid maturity and co-culture duration influenced results,while key factors for model optimization included tumor cell density,organoid age and extracellular matrix composition.Some studies also tested therapeutic strategies such as Zika virus and microRNA modulation.Collectively,findings support the utility of NOs as effective tools for studying GBM behavior and therapeutic responses in a humanized three-dimensional context.CONCLUSION Human NOs represent promising platforms for modeling glioblastoma invasion in a humanized three-dimensional environment.However,a limited number of studies and methodological heterogeneity hinder reproducibility.Protocol standardization is essential to enhance the translational application of these models.展开更多
D-D’-A type aza-borondipyrromethenes(aza-BODIPYs)were prepared by Suzuki cross-coupling reaction.Photothermal conversion efficiency of self-assemble aza-BODIPY-based nanoparticles(DA-azaBDP-NPs)with NIR-Ⅱ emission(...D-D’-A type aza-borondipyrromethenes(aza-BODIPYs)were prepared by Suzuki cross-coupling reaction.Photothermal conversion efficiency of self-assemble aza-BODIPY-based nanoparticles(DA-azaBDP-NPs)with NIR-Ⅱ emission(λ_(em)=1065 nm)was 37.2%under near infrared(NIR)irradiation,and the outstanding cytotoxicity was triggered by coexistence of DA-azaBDP-NPs and the NIR irradiation,with the decrease of glioblastoma migration and the inhibition of glioblastoma proliferation.DA-azaBDP-NPs could promote glioblastoma autophagy and accelerate the process of cell death.The photothermal therapy(PTT)of DAazaBDP-NPs can effectively induce glioblastoma death by apoptosis under the NIR irradiation,which is highly promising to be applied in vivo experiments of brain.展开更多
1.HOU J,DU Y,SHAO Y,et al.Identification,Albanol B inhibits glioblastoma progression by inducing senescence and apoptosis via the RNF6/p27 signaling axis.Phytomedicine.DOI:10.1016/j.phymed.2025.157056.(2025)[题目]Alba...1.HOU J,DU Y,SHAO Y,et al.Identification,Albanol B inhibits glioblastoma progression by inducing senescence and apoptosis via the RNF6/p27 signaling axis.Phytomedicine.DOI:10.1016/j.phymed.2025.157056.(2025)[题目]Albanol B通过RNF6/p27信号轴诱导细胞衰老与凋亡,从而抑制胶质母细胞瘤进展。展开更多
Herpes simplex virus thymidine kinase(HSVtk)gene therapy is a promising strategy for glioblastoma therapy.However,delivery of plasmid DNA(pDNA)encoding HSVtk into the brain by systemic administration is a challenge si...Herpes simplex virus thymidine kinase(HSVtk)gene therapy is a promising strategy for glioblastoma therapy.However,delivery of plasmid DNA(pDNA)encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the bloodbrain barrier.In this study,an exosome-membrane(EM)and polymer-based hybrid complex was developed for systemic delivery of pDNA into the brain.Histidine/arginine-linked polyamidoamine(PHR)was used as a carrier.PHR binds to pDNA by electrostatic interaction.The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid complex.For glioblastoma targeting,T7 peptide was attached to the pDNA/PHR-EM complex.Both pDNA/PHR-EM and T7-decorated pDNA/PHR-EM(pDNA/PHREM-T7)had a surface charge of–5 mV and a size of 280 nm.Transfection assays indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHREM.Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo.pHSVtk/PHR-EM-T7 had higher delivery efficiency than pHSVtk/PHR-EM.As a result,the HSVtk expression and apoptosis levels in the tumors of the pHSVtk/PHR-EM-T7 group were higher than those of the other control groups.Therefore,the pDNA/PHR-EM-T7 hybrid complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.展开更多
Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and mol...Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and molecular changes remain unclear.This study investigated platelet-derived growth factor receptor beta-positive(Pdgfrb+)pericyte dynamics and reprogramming in GBM vasculature.Methods:We generated GL261-Luc and GL261-CFP glioblastoma cells via lentiviral transduction and established two transgenic models.(1)For pericyte labeling,Ai14 reporter mice was crossed with PDGFRβ-P2A-CreERT2mice for td Tomato-specific lineage tracing(PT mice).(2)For conditional ablation,we generated inducible Pdgfrb-expressing cell ablation models(PT mice was crossed with ROSA-DTA mice).An intravital imaging platform(FITC-dextran/CFP/td Tomato+two-photon microscopy)tracked pericytes,vessels,and tumor cells,while FACSsorted Pdgfrb+cells from GBM and normal brain were analyzed by LC-MS/MS proteomics.Results:Cre-mediated ablation of Pdgfrb-expressing cells revealed stage-dependent effects on GBM growth:early ablation inhibited progression while late ablation promoted it.Pericytes undergo dual spatial reorganization in GBM:regional enrichment with pre-sprouting accumulation at the tumor-brain interface,and focal positioning with preferential localization at vascular branch points.Concurrently,GBM vasculature displayed simplified branching,dilation,and pericyte remodeling(shorter processes,higher density).Proteomics revealed 1426 altered proteins,with upregulated proliferation pathways(e.g.,matrix metallopeptidase 14[Mmp14],lysyl oxidase like 2[Loxl2])and downregulated homeostasis functions(e.g.,transforming growth factor beta 1[Tgfb1]),validated by scRNA-seq in human GBM.Conclusions:This study demonstrates that during early GBM progression,pericytes actively drive tumor angiogenesis through molecular reprogramming toward proliferative and pro-angiogenic phenotypes,with the integrated imaging-proteomics framework revealing potential therapeutic targets for disrupting pericyte-mediated vascular remodeling.展开更多
Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtyp...Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtype of extracellular vesicles are emerging as promising nanocarrier drug delivery systems to address these limitations.Exosomes released by all cell types can be easily obtained and modified as delivery vehicles or therapeutic agents.A systematic review was conducted to evaluate various methods for exosome isolation,characterization,engineering or modification,drug loading and delivery efficiency,including exosome biodistribution and treatment efficacy.A search of four databases for in vitro and in vivo studies(2000–,2023)identified 6165 records,of which 23 articles were found eligible and included for analyses.Most studies applied ultracentrifugation(UC)for exosomes isolation.Cancer cell lines being the most frequently used source of exosomes,followed by stem cells.The incubation approach was predominantly utilized to modify exosomes for drug loading.In vivo analysis showed that exosome biodistribution was primarily concentrated in the brain region,peaking in the first 6 h and remained moderately high.Compared to native exosomes and untreated control groups,utilizing modified native exosomes(cargo loaded)for treating glioblastoma disease models led to more pronounced suppression of tumor growth and proliferation,enhanced stimulation of immune response and apoptosis,effective restoration of drug chemosensitivity,increased anti-tumor effect and prolonged survival rates.Modified exosomes whether through incubation,sonication,transfection,freeze-thawing or their combination,improve targeted delivery and therapeutic efficacy against glioblastoma.展开更多
Glioblastoma(GBM)remains a major clinical challenge due to limited therapeutic success despite standard treatments including surgery,radiotherapy,and temozolomide(TMZ).Recent evidence links hyperglycemia to cancer pro...Glioblastoma(GBM)remains a major clinical challenge due to limited therapeutic success despite standard treatments including surgery,radiotherapy,and temozolomide(TMZ).Recent evidence links hyperglycemia to cancer progression,and altered glucose metabolism has emerged as a key factor in GBM development.Metformin,an antidiabetic drug,has shown promise in improving survival in GBM patients,possibly due to its ability to cross the blood-brain barrier and target metabolic pathways involved in tumor growth.Preclinical studies suggest metformin may enhance TMZ efficacy by acting on glioma stem cells and overcoming resistance mechanisms.Its activation of AMPK and modulation of Wnt signaling further support its therapeutic potential.However,while early studies and clinical trials have explored metformin’s safety and efficacy,its direct impact on GBM survival remains unclear.Ongoing research aims to clarify its mechanisms and identify responsive patient subgroups.Novel strategies,including PPARγagonists and nanoerythrosome-based drug delivery systems,are also under investigation to improve metformin’s therapeutic profile.Rigorous clinical trials and mechanistic studies are essential to determine the role of metformin as adjunct therapy in GBM treatment.展开更多
Glioblastoma multiforme(GBM)are the most aggressive and common tumors in the central nervous system.GBM are classified as grade IV according to the World Health Organization.The incidence of GBM slightly differs among...Glioblastoma multiforme(GBM)are the most aggressive and common tumors in the central nervous system.GBM are classified as grade IV according to the World Health Organization.The incidence of GBM slightly differs among countries.The etiology of GBM has not been entirely clarified.No risk factors such as smoking,chemicals or dietary can be identified for GBM.Only the exposure to high radiation dose such as radiotherapy of head and neck cancers have been reported to increase the risk of glioma tumors.In this review,the authors attempted to cover several aspects of GBM.This review was based on a collection of recent publications from different research fields but all related to GBM in order to shed the light on this disease.We highlighted the current insights of GBM in the aspects of epidemiology,pathogenesis,etiology,molecular genetics,imaging technologies,artificial intelligence and treatment.A literature review was conducted for GBM with relevant keywords.Although GBM was known since several decades,its causes are still confounding,and its early detection is often unpredictable.Since the hereditary aspect of GBM is very low,there remains as the common symptoms the interference with normal brain function,memory loss,unusual behavior,headaches and seizures.The progress in GBM treatment is not satisfactory even with the deployment of huge efforts and financial costs in many domains like gene therapy,surgery and chemoradiotherapy.Despite the rapid developments of the standard treatment for GBM,the trend of survival rate did not change among years.展开更多
文摘OBJECT:Glioblastoma multiforme(GBM)is the most common and lethal primary brain tumor in adults.It isnearly uniformly fatal,with a median survival time of approximately l year,despite modem treatment modalities.Nevertheless,a range of survival times exists around this median.Efforts to understand why some patients livelonger or shorter than the average may provide insight into the biology of these neoplasms.The annexin VII(ANX7)gene is located on the human chromosome 10q21,a site long hypothesized to harbor tumor
基金supported by the National Key Research and Development Programs of China(Grant No.2018YFA0209700)National Natural Science Foundation of China(Grant No.22077073)+1 种基金Frontiers Science Center for New Organic Matter,Nankai University(Grant No.63181206)the Fundamental Research Funds for the Central Universities,Nankai University(Grant No.63206015)。
文摘Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure.Mechanisms underlying the development of resistance involve multiple factors,including drug efflux,DNA damage repair,glioma stem cells,and a hypoxic tumor environment,which are usually correlative and promote each other.As many potential therapeutic targets have been discovered,combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy.In recent years,nanomedicine has revolutionized cancer therapies with optimized accumulation,penetration,internalization,and controlled release.Blood-brain barrier(BBB)penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB.Moreover,different drugs for combination therapy usually process different pharmacokinetics and biodistribution,which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies.Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed.This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.
基金supported by the National Natural Science Foundation of China(Grant Nos.82072765 to X.Q.and 82172667 to X.W.).
文摘Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 81272782）.
文摘Background Recent studies have suggested that cancer stem cells are one of the major causes for tumor recurrence due to their resistance to radiotherapy and chemotherapy. Although the highly invasive nature of glioblastoma （GBM） cells is also implicated in the failure of current therapies, it is not clear how glioma stem cells （GSCs） are involved in invasiveness. Racl activity is necessary for inducing reorganization of actin cytoskeleton and cell movement. In this study, we aimed to investigate the distribution characteristics of CD133＋ cells and Racl＋ cells in GBM as well as Racl activity in CD133＋ GBM cells, and analyze the migration and invasion potential of these cells. Methods A series of 21 patients with GBM were admitted consecutively and received tumor resection in Tianjin Medical University General Hospital during the first half of the year 2011. Tissue specimens were collected both from the peripheral and the central parts for each tumor under magnetic resonance imaging （MRI） navigation guidance. Immunohistochemical staining was used to detect the CD133＋ cells and Racl＋ cells distribution in GBM specimens. Double-labeling immunofluorescence was further used to analyze CD133 and Racl co-expression and the relationship between CD133＋ cells distribution and Racl expression. Serum-free medium culture and magnetic sorting were used to isolate CD133＋ cells from U87 cell line. Racl activation assay was conducted to assess the activation of Racl in CD133＋ and CD133- U87 cells. The migration and invasive ability of CD133＋ and CD133- U87 cells were determined by cell migration and invasion assays in vitro. Student＇s t-test and one-way analysis of variance （ANOVA） test were used to determine statistical significance in this study. Results In the central parts of GBMs, CD133＋ cells were found to cluster around necrosis and occasionally cluster around the vessels under the microscope by immunohistological staining. In the peripheral parts of the tumors, CD133＋ cells were lined up along the basement membrane of the vessels and myelinated nerve fibers. Racl expression was high and diffused in the central parts of the GBMs, and the Racl＋ cells were distributed basically in accordance with CD133＋ cells both in the central and peripheral parts of GBMs. In double-labeling immunofluorescence, Racl was expressed in （83.14＋4.23）% of CD133＋ cells, and CD133 and Racl co-expressed cells were located around the vessels in GBMs. Significantly higher amounts of Racl-GTP were expressed in the CD133＋ cells （0.378±0.007）, compared to CD133- cells （0.195±0.004） （t=-27.81; P 〈0.05）. CD133＋ cells had stronger ability to migrate （74.34±2.40 vs. 38.72±2.60, t=42.71, P 〈0.005） and invade （52.00±2.28 vs. 31.26±1.82, t=30.76, P 〈0.005）, compared to their counterpart CD133- cells in transwell cell migration/invasion assay. Conclusions These data suggest that CD133＋ GBM cells highly express Racl and have greater potential to migrate and invade through activated Racl-GTP. The accordance of distribution between Racl＋ cells and CD133＋ cells in GBMs implies that Racl might be an inhibited target to prevent invasion and migration and to avoid malignant glioma recurrence
基金the Beatrice Hunter Cancer Research Institutethe Brain Tumour Foundation of Canada
文摘Glioblastoma multiforme （GBM） is the most common adult primary tumor of the cen- tral nervous system. The current standard of care for glioblastoma patients involves a combination of surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide. Several mech- anisms underlying the inherent and acquired temozolomide resistance have been identified and con- tribute to treatment failure. Early identification of temozolomide-resistant GBM patients and improvement of the therapeutic strategies available to treat this malignancy are of uttermost impor- tance. This review initially looks at the molecular pathways underlying GBM formation and devel- opment with a particular emphasis placed on recent therapeutic advances made in the field. Our focus will next be directed toward the molecular mechanisms modulating temozolomide resistance in GBM patients and the strategies envisioned to circumvent this resistance. Finallyl we highlight the diagnostic and prognostic value of metabolomics in cancers and assess its potential usefulness in improving the current standard of care for GBM patients.
文摘Human cytomegalovirus (HCMV) was reported in glioblastoma multiforme (GBM) over a decade ago and this finding has the potential to increase our understanding of the disease and it offers an alternative tumor-specific therapeutic target. Due of this promise, there is a fair amount of time, energy and money being directed towards understanding and utilizing this connection for eventual therapeutic purposes. Nevertheless, the association between GBM and HCMV remains controversial. Several studies have reported conflicting results, further undermining the potential clinical value of this association. In this review, the authors will discuss the latest developments on this evolving issue. Specifically, the results of the latest studies, both positive and negative, will be discussed. Furthermore, potential theories to explain discrepancies reported in the literature will be proposed. Clinical implications including potential targets for anti-HCMV therapy and the latest developments in anti-HCMV therapy will be presented. Finally, solutions to remedy this controversial issue in neuro-oncology will be offered.
基金This work was supported by the Oklahoma Medical Research Foundation,and Oblato,Inc.,as reported in published manuscripts.
文摘The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an anti-angiogenic therapy[an antibody against the vascular endothelial growth factor(bevacizumab;Avastin)],resulting in recurrent tumors.Several recurrent GBM tumors are commonly resistant to either TMZ,radiation or bevacizumab,which contributes to the low survival rate for GBM patients.This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance.One of these therapeutic options is a small molecule called OKlahoma Nitrone 007(OKN-007),which was discovered to inhibit the transforming growth factor β1 pathway,reduce TMZ-resistance and enhance TMZ-sensitivity.OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients.Another novel target is ELTD1(epidermal growth factor,latrophilin and seven transmembrane domain-containing protein 1;alternatively known as ADGRL4,Adhesion G protein-coupled receptor L4),which we used a monoclonal antibody against,where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model.Notch 1 is known to be associated with chemoresistance in GBM.Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway,nuclear factor-κB,the hepatocyte/scatter factor(c-MET),the epidermal growth factor receptor,and the tumor microenvironment.
基金supported by grants from the National Natural Science Foundation of China(Nos.31970676,31970770,32270876)the National Key R&D Program of China(No.2018 YFA0800700,2022YFA0806600),and the Fundamental Research Funds for the Central Universities.
文摘Glioblastoma multiforme(GBM),a highly malignant and heterogeneous brain tumor,contains various types of tumor and non-tumor cells.Whether GBM cells can trans-differentiate into non-neural cell types,including mural cells or endothelial cells(ECs),to support tumor growth and invasion remains controversial.Here we generated two genetic GBM models de novo in immunocompetent mouse brains,mimicking essential pathological and molecular features of human GBMs.Lineage-tracing and transplantation studies demonstrated that,although blood vessels in GBM brains underwent drastic remodeling,evidence of trans-differentiation of GBM cells into vascular cells was barely detected.Intriguingly,GBM cells could promiscuously express markers for mural cells during gliomagenesis.Furthermore,single-cell RNA sequencing showed that patterns of copy number variations(CNVs)of mural cells and ECs were distinct from those of GBM cells,indicating discrete origins of GBM cells and vascular components.Importantly,single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages.Rather than expansion owing to trans-differentiation,vascular cell expanded by proliferation during tumorigenesis.Therefore,cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis.Our findings advance understanding of cell lineage dynamics during gliomagenesis,and have implications for targeted treatment of GBMs.
文摘Glioblastoma(GBM)is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking,followed by radiation therapy with concurrent and adjuvant temozolomide treatment.The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy.Several mechanisms including inter-and intratumoral heterogeneity,the evolution of therapy-resistant clonal subpopulations,reacquisition of stemness in glioblastoma stem cells,multiple drug efflux mechanisms,the tumor-promoting microenvironment,metabolic adaptations,and enhanced repair of drug-induced DNA damage have been implicated in therapy failure.Extracellular vesicles(EVs)have emerged as crucial mediators in the maintenance and establishment of GBM.Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance.Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies.In this review,we discuss the various mechanisms of therapy resistance in GBM,highlighting the emerging role of EV-orchestrated drug resistance.Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.
基金supported by Project of the Health Shanghai Initiative Special Fund(Medical-Sports Integration,Creating a New Model of Exercise for Health),No.JKSHZX-2022-02(to SC).
文摘Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of SUMOylation.We used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers.We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by nutlin-3.This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation.Using comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma progression.We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation.Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway.Its efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or exercise.Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation.Notably,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells.These results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma management.Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.
基金Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico,No.307318/2023-0 and No.102035/2024-5Fundação de AmparoàPesquisa do Estado de São Paulo,No.2023/10843-7 and No 2019/21070-3Nanotechnology National Laboratory System 2.0,Ministry of Science,Technology,Innovation and Communication,No.442539/2019-3.
文摘BACKGROUND Glioblastoma multiforme(GBM)is the most aggressive and prevalent primary malignant brain tumor in adults,marked by poor prognosis and high invasiveness.Traditional GBM invasion assays,such as those involving mouse brain xenografts,are often time-consuming and limited in efficiency.In this context,stem cell-derived neural organoids(NOs)have emerged as advanced,threedimensional,human-relevant platforms that mimic the cellular architecture and microenvironment of the human brain.These models provide novel opportunities to investigate glioblastoma stem cell invasion,a critical driver of tumor progression and therapeutic resistance.AIM To evaluate studies using stem cell-derived NOs to model glioblastoma migration/invasion,focusing on methodologies,applications and therapeutic implications.METHODS We conducted a systematic review following PRISMA guidelines,searching PubMed and Scopus for studies published between March 2019 and March 2025 that investigated NOs in the context of glioblastoma invasion/migration.After screening 377 articles based on predefined inclusion and exclusion criteria,10 original research articles were selected for analysis.Extracted data were categorized into four analytical domains:(1)Tumor model formation;(2)NO characteristics;(3)NO differentiation protocols;and(4)Invasion/migration assessment methodologies.RESULTS The included studies exhibit significant methodological heterogeneity GBM model development,particularly regarding model type,cell source and culture conditions.Most studies(70%)used suspension cell models,while 30%employed spheroids,with most research focusing on patient-derived glioblastoma stem cells.NOs were predominantly generated from human induced pluripotent stem cells using both guided and unguided differentiation protocols.Confocal fluorescence microscopy was the primary method used for assessing invasion,revealing invasion depths of up to 300μm.Organoid maturity and co-culture duration influenced results,while key factors for model optimization included tumor cell density,organoid age and extracellular matrix composition.Some studies also tested therapeutic strategies such as Zika virus and microRNA modulation.Collectively,findings support the utility of NOs as effective tools for studying GBM behavior and therapeutic responses in a humanized three-dimensional context.CONCLUSION Human NOs represent promising platforms for modeling glioblastoma invasion in a humanized three-dimensional environment.However,a limited number of studies and methodological heterogeneity hinder reproducibility.Protocol standardization is essential to enhance the translational application of these models.
基金supported by the National Natural Science Foundation of China(Nos.22078201,U1908202)Liaoning&Shenyang Key Laboratory of Functional Dye and Pigment(Nos.2021JH13/10200018,21-104-0-23).
文摘D-D’-A type aza-borondipyrromethenes(aza-BODIPYs)were prepared by Suzuki cross-coupling reaction.Photothermal conversion efficiency of self-assemble aza-BODIPY-based nanoparticles(DA-azaBDP-NPs)with NIR-Ⅱ emission(λ_(em)=1065 nm)was 37.2%under near infrared(NIR)irradiation,and the outstanding cytotoxicity was triggered by coexistence of DA-azaBDP-NPs and the NIR irradiation,with the decrease of glioblastoma migration and the inhibition of glioblastoma proliferation.DA-azaBDP-NPs could promote glioblastoma autophagy and accelerate the process of cell death.The photothermal therapy(PTT)of DAazaBDP-NPs can effectively induce glioblastoma death by apoptosis under the NIR irradiation,which is highly promising to be applied in vivo experiments of brain.
文摘1.HOU J,DU Y,SHAO Y,et al.Identification,Albanol B inhibits glioblastoma progression by inducing senescence and apoptosis via the RNF6/p27 signaling axis.Phytomedicine.DOI:10.1016/j.phymed.2025.157056.(2025)[题目]Albanol B通过RNF6/p27信号轴诱导细胞衰老与凋亡,从而抑制胶质母细胞瘤进展。
基金supported by the Individual Basic Science&Engineering Research Program(NRF-2022R1A2B5B01001920)through the National Research Foundation,funded by the Ministry of Science and ICT in Korea.
文摘Herpes simplex virus thymidine kinase(HSVtk)gene therapy is a promising strategy for glioblastoma therapy.However,delivery of plasmid DNA(pDNA)encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the bloodbrain barrier.In this study,an exosome-membrane(EM)and polymer-based hybrid complex was developed for systemic delivery of pDNA into the brain.Histidine/arginine-linked polyamidoamine(PHR)was used as a carrier.PHR binds to pDNA by electrostatic interaction.The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid complex.For glioblastoma targeting,T7 peptide was attached to the pDNA/PHR-EM complex.Both pDNA/PHR-EM and T7-decorated pDNA/PHR-EM(pDNA/PHREM-T7)had a surface charge of–5 mV and a size of 280 nm.Transfection assays indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHREM.Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo.pHSVtk/PHR-EM-T7 had higher delivery efficiency than pHSVtk/PHR-EM.As a result,the HSVtk expression and apoptosis levels in the tumors of the pHSVtk/PHR-EM-T7 group were higher than those of the other control groups.Therefore,the pDNA/PHR-EM-T7 hybrid complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.
基金The National Key Research and Development Program of China,Grant/Award Number:2022YFF0710700Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01。
文摘Background:Glioblastoma(GBM)is a highly aggressive brain tumor characterized by aberrant angiogenesis and an immunosuppressive microenvironment.Pericytes are aberrantly recruited but their spatiotemporal roles and molecular changes remain unclear.This study investigated platelet-derived growth factor receptor beta-positive(Pdgfrb+)pericyte dynamics and reprogramming in GBM vasculature.Methods:We generated GL261-Luc and GL261-CFP glioblastoma cells via lentiviral transduction and established two transgenic models.(1)For pericyte labeling,Ai14 reporter mice was crossed with PDGFRβ-P2A-CreERT2mice for td Tomato-specific lineage tracing(PT mice).(2)For conditional ablation,we generated inducible Pdgfrb-expressing cell ablation models(PT mice was crossed with ROSA-DTA mice).An intravital imaging platform(FITC-dextran/CFP/td Tomato+two-photon microscopy)tracked pericytes,vessels,and tumor cells,while FACSsorted Pdgfrb+cells from GBM and normal brain were analyzed by LC-MS/MS proteomics.Results:Cre-mediated ablation of Pdgfrb-expressing cells revealed stage-dependent effects on GBM growth:early ablation inhibited progression while late ablation promoted it.Pericytes undergo dual spatial reorganization in GBM:regional enrichment with pre-sprouting accumulation at the tumor-brain interface,and focal positioning with preferential localization at vascular branch points.Concurrently,GBM vasculature displayed simplified branching,dilation,and pericyte remodeling(shorter processes,higher density).Proteomics revealed 1426 altered proteins,with upregulated proliferation pathways(e.g.,matrix metallopeptidase 14[Mmp14],lysyl oxidase like 2[Loxl2])and downregulated homeostasis functions(e.g.,transforming growth factor beta 1[Tgfb1]),validated by scRNA-seq in human GBM.Conclusions:This study demonstrates that during early GBM progression,pericytes actively drive tumor angiogenesis through molecular reprogramming toward proliferative and pro-angiogenic phenotypes,with the integrated imaging-proteomics framework revealing potential therapeutic targets for disrupting pericyte-mediated vascular remodeling.
基金supported by the Bridging Grant from Universiti Sains Malaysia (R501LR-RND003–0000001319–0000)funding through the Fundamental Research Grant Scheme (FRGS/1/2020/TK0/USM/02/32–6171275) awarded by the Ministry of Higher Education Malaysia
文摘Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtype of extracellular vesicles are emerging as promising nanocarrier drug delivery systems to address these limitations.Exosomes released by all cell types can be easily obtained and modified as delivery vehicles or therapeutic agents.A systematic review was conducted to evaluate various methods for exosome isolation,characterization,engineering or modification,drug loading and delivery efficiency,including exosome biodistribution and treatment efficacy.A search of four databases for in vitro and in vivo studies(2000–,2023)identified 6165 records,of which 23 articles were found eligible and included for analyses.Most studies applied ultracentrifugation(UC)for exosomes isolation.Cancer cell lines being the most frequently used source of exosomes,followed by stem cells.The incubation approach was predominantly utilized to modify exosomes for drug loading.In vivo analysis showed that exosome biodistribution was primarily concentrated in the brain region,peaking in the first 6 h and remained moderately high.Compared to native exosomes and untreated control groups,utilizing modified native exosomes(cargo loaded)for treating glioblastoma disease models led to more pronounced suppression of tumor growth and proliferation,enhanced stimulation of immune response and apoptosis,effective restoration of drug chemosensitivity,increased anti-tumor effect and prolonged survival rates.Modified exosomes whether through incubation,sonication,transfection,freeze-thawing or their combination,improve targeted delivery and therapeutic efficacy against glioblastoma.
文摘Glioblastoma(GBM)remains a major clinical challenge due to limited therapeutic success despite standard treatments including surgery,radiotherapy,and temozolomide(TMZ).Recent evidence links hyperglycemia to cancer progression,and altered glucose metabolism has emerged as a key factor in GBM development.Metformin,an antidiabetic drug,has shown promise in improving survival in GBM patients,possibly due to its ability to cross the blood-brain barrier and target metabolic pathways involved in tumor growth.Preclinical studies suggest metformin may enhance TMZ efficacy by acting on glioma stem cells and overcoming resistance mechanisms.Its activation of AMPK and modulation of Wnt signaling further support its therapeutic potential.However,while early studies and clinical trials have explored metformin’s safety and efficacy,its direct impact on GBM survival remains unclear.Ongoing research aims to clarify its mechanisms and identify responsive patient subgroups.Novel strategies,including PPARγagonists and nanoerythrosome-based drug delivery systems,are also under investigation to improve metformin’s therapeutic profile.Rigorous clinical trials and mechanistic studies are essential to determine the role of metformin as adjunct therapy in GBM treatment.
文摘Glioblastoma multiforme(GBM)are the most aggressive and common tumors in the central nervous system.GBM are classified as grade IV according to the World Health Organization.The incidence of GBM slightly differs among countries.The etiology of GBM has not been entirely clarified.No risk factors such as smoking,chemicals or dietary can be identified for GBM.Only the exposure to high radiation dose such as radiotherapy of head and neck cancers have been reported to increase the risk of glioma tumors.In this review,the authors attempted to cover several aspects of GBM.This review was based on a collection of recent publications from different research fields but all related to GBM in order to shed the light on this disease.We highlighted the current insights of GBM in the aspects of epidemiology,pathogenesis,etiology,molecular genetics,imaging technologies,artificial intelligence and treatment.A literature review was conducted for GBM with relevant keywords.Although GBM was known since several decades,its causes are still confounding,and its early detection is often unpredictable.Since the hereditary aspect of GBM is very low,there remains as the common symptoms the interference with normal brain function,memory loss,unusual behavior,headaches and seizures.The progress in GBM treatment is not satisfactory even with the deployment of huge efforts and financial costs in many domains like gene therapy,surgery and chemoradiotherapy.Despite the rapid developments of the standard treatment for GBM,the trend of survival rate did not change among years.
