Neural stem cells(NSCs)and glioblastoma stem cells(GSCs)share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression.While acetylcholine(ACh...Neural stem cells(NSCs)and glioblastoma stem cells(GSCs)share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression.While acetylcholine(ACh)regulates NSC quiescence and differentiation within neurogenic niches,glioblastoma cells exploit th ese pathways to enhance their adaptability and invasiveness.The involvement of muscarinic(M3)and nicotinic(α7)receptors in both cell types suggests that glioblastoma retains neural progenitor-like traits,contributing to its plasticity and resilience.This article explores the shared cholinergic mechanisms between NSCs and GSCs,highlighting their role in both neural development and glioblastoma progression.展开更多
Objectives Glioblastoma multiforme(GBM)is highly resistant to apoptosis.This study investigates the role of Selenoprotein M(SELENOM),a redox-regulating protein,in the response of human glioblastoma A-172 cells to stau...Objectives Glioblastoma multiforme(GBM)is highly resistant to apoptosis.This study investigates the role of Selenoprotein M(SELENOM),a redox-regulating protein,in the response of human glioblastoma A-172 cells to staurosporine(STS)and hyperthermia.Methods A stable SELENOM-knockdown(SELENOM-KD)cell line was created.We measured reactive oxygen species(ROS),mitochondrial membrane potential(ΔΨm),cell death,and apoptotic gene expression.Results SELENOM-KD increased basal ROS levels and induced mitochondrial dysfunction.It sensitized cells to STS-induced apoptosis,enhancing the upregulation of pro-apoptotic genes.Conversely,under hyperthermia(42°C),SELENOM-KD cells exhibited significant thermoresistance,with 52%survival vs.99%death in controls,associated with suppressed pro-apoptotic signaling.Conclusions SELENOM is a critical redox and mitochondrial regulator in GBM.Its loss produces a context-dependent effect on cell fate:sensitizing to chemical apoptosis while conferring resistance to hyperthermia.SELENOM expression is a promising predictive biomarker for stratifying GBM patients for hyperthermia-based therapies.展开更多
Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving resear...Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.展开更多
Diatoms,as natural sources of porous silica,have important potential for biomedical applications.Biohybrid microrobots also show promise for targeted delivery;however,research on converting diatoms into biohybrid micr...Diatoms,as natural sources of porous silica,have important potential for biomedical applications.Biohybrid microrobots also show promise for targeted delivery;however,research on converting diatoms into biohybrid microrobots and exploiting their intrinsic properties for cancer treatment remains limited.In this study,Thalassiosira weissflogii was transformed into biohybrid microrobots(Mag-Diatoms)while retaining its natural chlorophyll,thereby enabling Mag-Diatom-mediated photodynamic therapy(PDT)without additional drug modification.In this system,Mag-Diatoms act ed as microrobots,and their intrinsic chlorophyll serve d as a photosensitizer,exhibiting excellent biological safety.The autonomous closed-loop motion of the Mag-Diatoms was achieved using an artificial intelligence algorithm,which enabled controlled navigation along a preset trajectory.Mag-Diatoms also exhibited the ability to traverse narrow slits and target cancer cells within a cellular environment.The PDT effect was validated in vitro using human malignant glioblastoma(GBM)cell lines and primary cells derived from patients.The results revealed that the cell viability was closely related to the Mag-Diatom concentration,laser intensity,and irradiation time.Under combined Mag-Diatoms and laser treatment,viability decreased to 19.5%in primary cells and 3.6%in cell line models.Moreover,in vivo experiments using a mouse glioma model revealed that Mag-Diatom-mediated PDT effectively suppressed GBM progression.These findings highlight the potential of diatom-derived biohybrid microrobots,leveraging their natural properties,as a novel material and solution for PDT-based GBM therapy.展开更多
Objective:Glioblastoma(GB)therapy is challenged by tumor heterogeneity and multidrug resistance(MDR),highlighting the need for effective therapies.This study aimed to explore the combined anticancer effects of Sunitin...Objective:Glioblastoma(GB)therapy is challenged by tumor heterogeneity and multidrug resistance(MDR),highlighting the need for effective therapies.This study aimed to explore the combined anticancer effects of Sunitinib(SNB)and Fenofibrate(FEN)on U87 cells.Methods:U87 cells were exposed to SNB,FEN,or their combination for 24 h,followed by evaluations of cell viability,migration,and clonogenic survival using MTT,scratch,and colony formation assays.Intracellular reactive oxygen species(ROS)were quantified via the 2′,7′-dichlorofluorescein assay,while mitochondrial membrane potential(MMP)was assessed using JC-1 red/green fluorescence.Molecular docking was performed to investigate SNB and FEN interactions with multiple molecular targets,including topoisomerase II(TOP-II),c-Jun N-terminal kinase(JNK),histone deacetylase 2(HDAC2),cyclooxygenase-2(COX-2),matrix metalloproteinase-9(MMP-9),cytochrome P4503A4(CYP3A4),glutathione peroxidase 4(GPX4),glutathione Stransferase(GST),heme oxygenase-1(HO-1),and 5-lipoxygenase(5-LOX).Results:The results demonstrated that both SNB and FEN significantly reduced U87 cell viability,migration,and clonogenic potential,with the combination treatment exhibiting synergistic cytotoxicity.SNB alone markedly increased ROS levels,while FEN,individually or in combination,reduced oxidative stress.Although SNB diminished mitochondrial membrane potential,cotreatment with FEN restored MMP values close to control levels.Docking analyses revealed that SNB displayed strong affinities for TOP-II,JNK,and HDAC2,whereas FEN preferentially interacted with MMP-9,COX-2,CYP3A4,and GPX4,suggesting complementary mechanisms targeting oxidative stress,inflammation,and programmed cell death regulation.Conclusion:The combination of SNB and FEN represents a promising multi-targeted therapeutic approach against GB.SNB and FEN combination capable of modulating and reprogramming key molecular pathways involved in GB progression and MDR.展开更多
Glioblastoma(GBM),the most aggressive and lethal primary brain tumor in adults,continues to resist conventional therapeutic approaches,withmedian survival remaining dismally low.Immune checkpoint inhibitors(ICIs),whic...Glioblastoma(GBM),the most aggressive and lethal primary brain tumor in adults,continues to resist conventional therapeutic approaches,withmedian survival remaining dismally low.Immune checkpoint inhibitors(ICIs),which have revolutionized the treatment of several solid tumors,have shown limited efficacy inGBMowing to the highly immunosuppressive and heterogeneousmicroenvironment of the tumor.The unique immune landscape of the central nervous system(CNS),characterized by low immunogenicity,restricted T-cell infiltration,and an abundance of regulatory and myeloid-derived suppressor cells,poses considerable barriers to effective immune reactivation.This review provides a comprehensive synthesis of the mechanistic barriers undermining ICI efficacy in GBM,including the blood-brain barrier,low tumor mutational burden,adaptive immune resistance,and iatrogenic immunosuppression.It also explores emerging predictive and prognostic biomarkers,such as programmed death-ligand 1(PD-L1)expression,immune gene signatures,tumor-infiltrating lymphocyte profiles,and circulating markers in cerebrospinal fluid and plasma,which hold promise for guiding patient selection and therapeutic monitoring.Importantly,recent breakthroughs in combinatorial immunotherapy strategies are highlighted,including the integration of ICIs with radiotherapy,anti-angiogenic agents,oncolytic viruses,personalized neoantigen vaccines,and tumor microenvironment reprogramming approaches.Innovative delivery platforms,such as nanoparticles,focused ultrasound,and convection-enhanced delivery,are also discussed for their potential to improve drug bioavailability and local immune activation in the CNS.This review hypothesizes that the therapeutic efficacy of ICIs in GBM can be considerably enhanced by disrupting immune exclusion and reversing immunosuppression through integrated,multimodal strategies guided by dynamic biomarker profiling and spatially resolved immunemapping.This hypothesisdriven approach aims to bridge translational gaps and inform next-generation clinical trial designs that may unlock the potential of immunotherapy for GBM.展开更多
Objectives:Glioblastoma(GBM)is a prevalent malignant brain tumor prone to drug resistance.We previously found a strong correlation between SH3 domain GRB2-like endophilin B1(SH3GLB1)and superoxide dismutase 2(SOD2),wh...Objectives:Glioblastoma(GBM)is a prevalent malignant brain tumor prone to drug resistance.We previously found a strong correlation between SH3 domain GRB2-like endophilin B1(SH3GLB1)and superoxide dismutase 2(SOD2),which converts O_(2)to hydrogen peroxide(H_(2)O_(2)).Prior studies show that H_(2)O_(2)redox signaling is vital for physiological processes and can drive tumor progression.Therefore,we aim to define how H_(2)O_(2)signaling regulates SH3GLB1 and AKT(protein kinase B)pathways in GBM and to assess whether modulating H_(2)O_(2)reverses temozolomide(TMZ)resistance.Methods:We used cultured cells and pharmacological inhibitors and activators to confirm the significance of H_(2)O_(2)signaling.GBM cells were used to verify the role of H_(2)O_(2)signaling in cell state transitions and animal experiments identified optimal treatment strategies.Results:We found that SOD2 acts as an upstream regulator of SH3GLB1.When SOD inhibitors and TMZ were combined,cells showed reduced SH3GLB1 and autophagy levels.SH3GLB1 was found to be regulated by H_(2)O_(2)via AKT signaling using redox homeostasis-regulating experiments.Although treatment-induced changes in mitochondrial H_(2)O_(2)levels mirrored those in the cytosol,parental and resistant cells exhibited divergent fates,highlighting cell-fate plasticity.TMZ combined with a redox modulator reduced resistant tumor cell growth(about 2/3 reduction of tumor size;p<0.05)and suppressed SH3GLB1 and autophagy levels in animal models.The TMZ-induced increase in SH3GLB1 expression was reversed by HgCl2,which inhibited the aquaporin-9/AKT signaling.Conclusion:Overall,these findings underscore the importance of H_(2)O_(2)-SH3GLB1 signaling in GBM and may inform future therapeutic strategies for overcoming TMZ resistance.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
Background:Microglia and brain macrophages contribute significantly to the tumor microenvironment in highly malignant glioblastoma where they are considered important drivers of tumor progression.A better understandin...Background:Microglia and brain macrophages contribute significantly to the tumor microenvironment in highly malignant glioblastoma where they are considered important drivers of tumor progression.A better understanding of the role of the brain macrophages present in glioblastoma appears crucial for improving therapeutic outcomes,especially in the context of novel immunotherapeutic approaches.Methods:We investigated the regulation of two well-established markers for microglia and brain macrophages,IBA1 and CD163,in relation to glioblastoma tumor necrosis using immunohistochemistry and modality fusion heatmaps of whole slide images obtained from adjacent tissue sections.Results:IBA1 and CD163 showed remarkable differences in relation to glioblastoma tumor necrosis.Generally,IBA1 immunoreactive cells were far less common in necrotic tissue areas than CD163-expressing cells.We also found extensive and frequently diffuse extracellular CD163 deposition,especially in hypocellular necrobiotic tumor regions where IBA1 was typically absent.Conclusions:Resident microglia seem more likely to be important for the diffuse infiltration of glioma cells in hypercellular tissue areas,whereas myeloid macrophages may be the main macrophage population in the wake of tumor necrosis.Since the necrotic niche with its interactions between microglia,brain macrophages,and glioblastoma/glioma stem cells is increasingly recognised as an important factor in tumor progression,further detailed studies of the macrophage populations in glioblastoma are warranted.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
Objectives:Cisplatin(CDDP)therapy for glioblastoma(GBM)is linked with several limitations,which include poor penetration of the blood-brain barrier(BBB),systemic toxicity,and the development of drug resistance mechani...Objectives:Cisplatin(CDDP)therapy for glioblastoma(GBM)is linked with several limitations,which include poor penetration of the blood-brain barrier(BBB),systemic toxicity,and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways.This study evaluates C-Phycocyanin(C-PC)as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis.Methods:GBM cells(U87 and U87-EGFRvIII)were treated with CDDP,C-PC,or their combination.Cell viability was assessed by MTT assay;apoptosis was evaluated by DAPI staining andWestern blot analysis of cleaved Caspase-3 and poly(ADP-ribose)polymerase(PARP).Both intracellular and extracellular reactive oxygen species(ROS)were measured using 2′,7′-dichlorodihydrofluorescein diacetate(DCF-DA)fluorescence and lucigenin chemiluminescence,respectively.Catalase activity was quantified via hydrogen peroxide(H2O2)decomposition assay,and manganese superoxide dismutase(MnSOD)expression byWestern blot.Results:C-PCselectively decreased U87GBMcell viability while sparing normal cells.C-PC enhanced CDDP cytotoxicity,reducing viability to 26.5%vs.53.2%for CDDP alone.This effect correlated with increased apoptosis,evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels.Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity.In U87-EGFRvIII cells,CDDP reduced viability modestly(85.2%),C-PC alone decreased viability significantly(51.5%)and induced cell death,but the combination did not further increase apoptosis.Here,C-PC’s pro-apoptotic effects,alone or with CDDP,were also associated with reduced oxidative stress in cells.Conclusion:We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS,suggesting potential for improved therapeutic efficacy with reduced systemic toxicity.Compared to the combination,C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells,underscoring its potential as a standalone therapeutic approach for chemotherapy-resistant glioblastoma subtypes.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
Background:Glioblastoma(GBM)remains themost aggressive primary brain tumour in adults,marked by pronounced cellular heterogeneity,diffuse infiltration,and resistance to conventional treatment.In recent years,transcrip...Background:Glioblastoma(GBM)remains themost aggressive primary brain tumour in adults,marked by pronounced cellular heterogeneity,diffuse infiltration,and resistance to conventional treatment.In recent years,transcriptomic profiling has provided valuable insights into the molecular mechanisms that govern the progression of glioblastoma.This systematic review aims to synthesise the current literature on dysregulated gene expression in GBM,focusing on gene signatures associatedwith stemness,immunemodulation,extracellularmatrix remodelling,metabolic adaptation,and therapeutic resistance.Methods:We conducted a systematic search of PubMed,The Cancer Genome Atlas(TCGA),Chinese Glioma Genome Atlas(CGGA),and the GlioVis portal for studies published between January 2005 and April 2025,limited to English-language reports.Studies were eligible if they included adult glioblastoma tissue or patient-derived datasets and reported gene-level expression or clinical associations.Reviews,commentaries,and studies on non-GBM gliomas were excluded.Screening followed the PRISMA 2020 checklist,with 410 records initially identified,90 duplicates removed,and 125 studies retained after full-text review.Data were synthesised descriptively,and findings were validated against TCGA/CGGA expression datasets to ensure consistency across cohorts.Results:We categorised recurrently dysregulated genes by their biological function,including transcription factors(SOX2,ZEB2),growth factor receptors(EGFR,PDGFRA),immune-related markers(PD-L1,TAP1,B2M),extracellular matrix regulators(MMP2,LAMC1,HAS2),and metabolic genes(SLC7A11,PRMT5,NRF2).For each group,we examine the functional consequences of transcriptional alterations and their role in driving key glioblastoma phenotypes,including angiogenesis,immunosuppression,invasiveness,and recurrence.Conclusion:We further discuss the prognostic implications of these gene signatures and evaluate their potential utility in precisionmedicine,including current clinical trials that target molecular pathways identified through transcriptomic data.This review highlights the power of gene expression profiling to stratify glioblastoma subtypes and improve personalised therapeutic strategies.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
Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the util...Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography(PET/CT)remains limited.This investigation involved the synthesis of[18F]AlF-NOTA-PCP2,which is a novel peptide-based radiolabeled tracer that targets PD-L1,and evaluated its imaging capabilities in orthotopic glioblastoma(GBM)models.Using this tracer,we could noninvasively monitor radiation-induced PD-L1 changes in GBM.[18F]AlF-NOTA-PCP2 exhibited high radiochemical purity(>95%)and stability up to 4 h after synthesis.It demonstrated specific,high-affinity binding to PD-L1 in vitro and in vivo,with a dissociation constant of 0.24 nM.PET/CT imaging,integrated with contrast-enhanced magnetic resonance imaging,revealed significant accumulation of[18F]AlF-NOTA-PCP2 in orthotopic tumors,correlating with blood-brain barrier disruption.After radiotherapy(15 Gy),[18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51%±0.73%to 12.04%±1.43%,indicating enhanced PD-L1 expression consistent with immunohistochemistry findings.Fractionated radiation(5 Gy×3)further amplified PD-L1 upregulation(13.9%±1.54%ID/cc)compared with a single dose(11.48%±1.05%ID/cc).Taken together,[18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.展开更多
Objectives:Glioblastoma is a prevalent malignant brain tumor,and the actions of the long non-coding RNA HOXA10-AS in its invasion and migration remain unclear.Here,the function of HOXA10-AS in glioblastoma cell invasi...Objectives:Glioblastoma is a prevalent malignant brain tumor,and the actions of the long non-coding RNA HOXA10-AS in its invasion and migration remain unclear.Here,the function of HOXA10-AS in glioblastoma cell invasion and migration and associated mechanisms were investigated.Methods:HOXA10-AS was knocked down in glioblastoma cells,and Transwell and wound healing assays were conducted to elucidate its impacts on cell invasion and migration.Western blotting and quantitative reverse transcription polymerase chain reaction(qRTPCR)assessed HOXA10-AS’s impact on the epithelial-mesenchymal transition(EMT).Microarray analysis identified differentially expressed genes,complemented by bioinformatics approaches to explore potentialmolecular participants and pathways.Rescue experiments validated our findings.Results:HOXA10-AS knockdown significantly inhibits glioblastoma cell migration,invasion,and the EMT process.Specifically,HOXA10-AS siRNA transfection significantly reduced the migratory capacity of A172 cells by 50.5%and U251 cells by 61.4%,as well as their invasive capacities by 33.8%and 58.5%,respectively(all p<0.05).HOXA10-AS acts as anmiR-99a-3p sponge,and pathway analysis identified processes linked to tumorigenesis andmetastasis,alongwith nine hub genes.HOXA10-AS upregulates the expression of integrin subunit beta 5(ITGB5)through a competing endogenous RNAmechanism.Thereduced tumorigenic behavior of glioblastoma cells due toHOXA10-AS knockdown can be rescued by ITGB5 overexpression ormiR-99a-3p inhibitor.Conclusion:These results indicate thatHOXA10-AS promotes tumorigenic behavior in glioblastoma cells by regulating the EMT-like process and functioning as an miR-99a-3p sponge to modulate ITGB5 levels,providing insights into glioblastoma development and potential therapeutic targets.展开更多
Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A ...Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A recent study published in Nature by Faust Akl and colleagues begins to lift the veil on this mystery,uncovering a previously unknown mechanism of immune evasion in GBM[3].展开更多
文摘Neural stem cells(NSCs)and glioblastoma stem cells(GSCs)share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression.While acetylcholine(ACh)regulates NSC quiescence and differentiation within neurogenic niches,glioblastoma cells exploit th ese pathways to enhance their adaptability and invasiveness.The involvement of muscarinic(M3)and nicotinic(α7)receptors in both cell types suggests that glioblastoma retains neural progenitor-like traits,contributing to its plasticity and resilience.This article explores the shared cholinergic mechanisms between NSCs and GSCs,highlighting their role in both neural development and glioblastoma progression.
基金the framework of the State assignment No.075-00607-25-00.
文摘Objectives Glioblastoma multiforme(GBM)is highly resistant to apoptosis.This study investigates the role of Selenoprotein M(SELENOM),a redox-regulating protein,in the response of human glioblastoma A-172 cells to staurosporine(STS)and hyperthermia.Methods A stable SELENOM-knockdown(SELENOM-KD)cell line was created.We measured reactive oxygen species(ROS),mitochondrial membrane potential(ΔΨm),cell death,and apoptotic gene expression.Results SELENOM-KD increased basal ROS levels and induced mitochondrial dysfunction.It sensitized cells to STS-induced apoptosis,enhancing the upregulation of pro-apoptotic genes.Conversely,under hyperthermia(42°C),SELENOM-KD cells exhibited significant thermoresistance,with 52%survival vs.99%death in controls,associated with suppressed pro-apoptotic signaling.Conclusions SELENOM is a critical redox and mitochondrial regulator in GBM.Its loss produces a context-dependent effect on cell fate:sensitizing to chemical apoptosis while conferring resistance to hyperthermia.SELENOM expression is a promising predictive biomarker for stratifying GBM patients for hyperthermia-based therapies.
基金supported by Key Research and Development Plan of Hunan Province(2024DK2006)the Fundamental Research Funds for the Central Universities of Central South University(1053320221769)+2 种基金Hunan Provincial Respiratory Disease Rehabilitation and Nursing Engineering Research Center Innovation Capacity Building Project(No.202012)the Zhangjiajie Science and Technology Development Key Special Project(No.202304)the National Key Clinical Specialty Major Scientific Research Project(No.20230382).
文摘Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.
基金supported by the National Key R&D Program of China(No.2023YFB4705600)the National Natural Science Foundation of China(Nos.U23A20342,U20A20380,62273331,62127811,and 82373342)+4 种基金CAS Project for Young Scientists in Basic Research(No.YSBR-036)New Cornerstone Science Foundation through the XPLORER PRIZE,CAS/SAFEA International Partnership Program for Creative Research Teams,the Science and Technology Planning Project of Liaoning Province(No.2021JH1/10400049)Shengjing Hospital of China Medical University 345 Talent Project(No.1000801592)the Joint Project of Liaoning Province(No.2023JH2/101700202)“the Fundamental Research Funds for the Central Universities”,South-Central Minzu University(No.CZQ 25014).
文摘Diatoms,as natural sources of porous silica,have important potential for biomedical applications.Biohybrid microrobots also show promise for targeted delivery;however,research on converting diatoms into biohybrid microrobots and exploiting their intrinsic properties for cancer treatment remains limited.In this study,Thalassiosira weissflogii was transformed into biohybrid microrobots(Mag-Diatoms)while retaining its natural chlorophyll,thereby enabling Mag-Diatom-mediated photodynamic therapy(PDT)without additional drug modification.In this system,Mag-Diatoms act ed as microrobots,and their intrinsic chlorophyll serve d as a photosensitizer,exhibiting excellent biological safety.The autonomous closed-loop motion of the Mag-Diatoms was achieved using an artificial intelligence algorithm,which enabled controlled navigation along a preset trajectory.Mag-Diatoms also exhibited the ability to traverse narrow slits and target cancer cells within a cellular environment.The PDT effect was validated in vitro using human malignant glioblastoma(GBM)cell lines and primary cells derived from patients.The results revealed that the cell viability was closely related to the Mag-Diatom concentration,laser intensity,and irradiation time.Under combined Mag-Diatoms and laser treatment,viability decreased to 19.5%in primary cells and 3.6%in cell line models.Moreover,in vivo experiments using a mouse glioma model revealed that Mag-Diatom-mediated PDT effectively suppressed GBM progression.These findings highlight the potential of diatom-derived biohybrid microrobots,leveraging their natural properties,as a novel material and solution for PDT-based GBM therapy.
基金funding program(ORF-2025-1037)at King Saud University,Riyadh,Saudi Arabia.
文摘Objective:Glioblastoma(GB)therapy is challenged by tumor heterogeneity and multidrug resistance(MDR),highlighting the need for effective therapies.This study aimed to explore the combined anticancer effects of Sunitinib(SNB)and Fenofibrate(FEN)on U87 cells.Methods:U87 cells were exposed to SNB,FEN,or their combination for 24 h,followed by evaluations of cell viability,migration,and clonogenic survival using MTT,scratch,and colony formation assays.Intracellular reactive oxygen species(ROS)were quantified via the 2′,7′-dichlorofluorescein assay,while mitochondrial membrane potential(MMP)was assessed using JC-1 red/green fluorescence.Molecular docking was performed to investigate SNB and FEN interactions with multiple molecular targets,including topoisomerase II(TOP-II),c-Jun N-terminal kinase(JNK),histone deacetylase 2(HDAC2),cyclooxygenase-2(COX-2),matrix metalloproteinase-9(MMP-9),cytochrome P4503A4(CYP3A4),glutathione peroxidase 4(GPX4),glutathione Stransferase(GST),heme oxygenase-1(HO-1),and 5-lipoxygenase(5-LOX).Results:The results demonstrated that both SNB and FEN significantly reduced U87 cell viability,migration,and clonogenic potential,with the combination treatment exhibiting synergistic cytotoxicity.SNB alone markedly increased ROS levels,while FEN,individually or in combination,reduced oxidative stress.Although SNB diminished mitochondrial membrane potential,cotreatment with FEN restored MMP values close to control levels.Docking analyses revealed that SNB displayed strong affinities for TOP-II,JNK,and HDAC2,whereas FEN preferentially interacted with MMP-9,COX-2,CYP3A4,and GPX4,suggesting complementary mechanisms targeting oxidative stress,inflammation,and programmed cell death regulation.Conclusion:The combination of SNB and FEN represents a promising multi-targeted therapeutic approach against GB.SNB and FEN combination capable of modulating and reprogramming key molecular pathways involved in GB progression and MDR.
文摘Glioblastoma(GBM),the most aggressive and lethal primary brain tumor in adults,continues to resist conventional therapeutic approaches,withmedian survival remaining dismally low.Immune checkpoint inhibitors(ICIs),which have revolutionized the treatment of several solid tumors,have shown limited efficacy inGBMowing to the highly immunosuppressive and heterogeneousmicroenvironment of the tumor.The unique immune landscape of the central nervous system(CNS),characterized by low immunogenicity,restricted T-cell infiltration,and an abundance of regulatory and myeloid-derived suppressor cells,poses considerable barriers to effective immune reactivation.This review provides a comprehensive synthesis of the mechanistic barriers undermining ICI efficacy in GBM,including the blood-brain barrier,low tumor mutational burden,adaptive immune resistance,and iatrogenic immunosuppression.It also explores emerging predictive and prognostic biomarkers,such as programmed death-ligand 1(PD-L1)expression,immune gene signatures,tumor-infiltrating lymphocyte profiles,and circulating markers in cerebrospinal fluid and plasma,which hold promise for guiding patient selection and therapeutic monitoring.Importantly,recent breakthroughs in combinatorial immunotherapy strategies are highlighted,including the integration of ICIs with radiotherapy,anti-angiogenic agents,oncolytic viruses,personalized neoantigen vaccines,and tumor microenvironment reprogramming approaches.Innovative delivery platforms,such as nanoparticles,focused ultrasound,and convection-enhanced delivery,are also discussed for their potential to improve drug bioavailability and local immune activation in the CNS.This review hypothesizes that the therapeutic efficacy of ICIs in GBM can be considerably enhanced by disrupting immune exclusion and reversing immunosuppression through integrated,multimodal strategies guided by dynamic biomarker profiling and spatially resolved immunemapping.This hypothesisdriven approach aims to bridge translational gaps and inform next-generation clinical trial designs that may unlock the potential of immunotherapy for GBM.
基金supported by research grants from the Ministry of Science and Technology(MOST 108-2314-B-400-026 and 109-2013-B-400-036)National Science and Technology Council(NSTC 112-2320-B-214-010 and 113-2320-B-214-002)I-Shou University(ISU-112-01-12A,ISU112-S-02 and ISU114-S-04).
文摘Objectives:Glioblastoma(GBM)is a prevalent malignant brain tumor prone to drug resistance.We previously found a strong correlation between SH3 domain GRB2-like endophilin B1(SH3GLB1)and superoxide dismutase 2(SOD2),which converts O_(2)to hydrogen peroxide(H_(2)O_(2)).Prior studies show that H_(2)O_(2)redox signaling is vital for physiological processes and can drive tumor progression.Therefore,we aim to define how H_(2)O_(2)signaling regulates SH3GLB1 and AKT(protein kinase B)pathways in GBM and to assess whether modulating H_(2)O_(2)reverses temozolomide(TMZ)resistance.Methods:We used cultured cells and pharmacological inhibitors and activators to confirm the significance of H_(2)O_(2)signaling.GBM cells were used to verify the role of H_(2)O_(2)signaling in cell state transitions and animal experiments identified optimal treatment strategies.Results:We found that SOD2 acts as an upstream regulator of SH3GLB1.When SOD inhibitors and TMZ were combined,cells showed reduced SH3GLB1 and autophagy levels.SH3GLB1 was found to be regulated by H_(2)O_(2)via AKT signaling using redox homeostasis-regulating experiments.Although treatment-induced changes in mitochondrial H_(2)O_(2)levels mirrored those in the cytosol,parental and resistant cells exhibited divergent fates,highlighting cell-fate plasticity.TMZ combined with a redox modulator reduced resistant tumor cell growth(about 2/3 reduction of tumor size;p<0.05)and suppressed SH3GLB1 and autophagy levels in animal models.The TMZ-induced increase in SH3GLB1 expression was reversed by HgCl2,which inhibited the aquaporin-9/AKT signaling.Conclusion:Overall,these findings underscore the importance of H_(2)O_(2)-SH3GLB1 signaling in GBM and may inform future therapeutic strategies for overcoming TMZ resistance.
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.
基金funding but aspects of this work(computer analysis)were supported by an Australian Research Council(ARC)grant,DP150104472(MBG)The Australian Genomics and Outcomes of Glioma project was funded by a Cancer Council NSW Strategic Research Partnership Grant.
文摘Background:Microglia and brain macrophages contribute significantly to the tumor microenvironment in highly malignant glioblastoma where they are considered important drivers of tumor progression.A better understanding of the role of the brain macrophages present in glioblastoma appears crucial for improving therapeutic outcomes,especially in the context of novel immunotherapeutic approaches.Methods:We investigated the regulation of two well-established markers for microglia and brain macrophages,IBA1 and CD163,in relation to glioblastoma tumor necrosis using immunohistochemistry and modality fusion heatmaps of whole slide images obtained from adjacent tissue sections.Results:IBA1 and CD163 showed remarkable differences in relation to glioblastoma tumor necrosis.Generally,IBA1 immunoreactive cells were far less common in necrotic tissue areas than CD163-expressing cells.We also found extensive and frequently diffuse extracellular CD163 deposition,especially in hypocellular necrobiotic tumor regions where IBA1 was typically absent.Conclusions:Resident microglia seem more likely to be important for the diffuse infiltration of glioma cells in hypercellular tissue areas,whereas myeloid macrophages may be the main macrophage population in the wake of tumor necrosis.Since the necrotic niche with its interactions between microglia,brain macrophages,and glioblastoma/glioma stem cells is increasingly recognised as an important factor in tumor progression,further detailed studies of the macrophage populations in glioblastoma are warranted.
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Objectives:Cisplatin(CDDP)therapy for glioblastoma(GBM)is linked with several limitations,which include poor penetration of the blood-brain barrier(BBB),systemic toxicity,and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways.This study evaluates C-Phycocyanin(C-PC)as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis.Methods:GBM cells(U87 and U87-EGFRvIII)were treated with CDDP,C-PC,or their combination.Cell viability was assessed by MTT assay;apoptosis was evaluated by DAPI staining andWestern blot analysis of cleaved Caspase-3 and poly(ADP-ribose)polymerase(PARP).Both intracellular and extracellular reactive oxygen species(ROS)were measured using 2′,7′-dichlorodihydrofluorescein diacetate(DCF-DA)fluorescence and lucigenin chemiluminescence,respectively.Catalase activity was quantified via hydrogen peroxide(H2O2)decomposition assay,and manganese superoxide dismutase(MnSOD)expression byWestern blot.Results:C-PCselectively decreased U87GBMcell viability while sparing normal cells.C-PC enhanced CDDP cytotoxicity,reducing viability to 26.5%vs.53.2%for CDDP alone.This effect correlated with increased apoptosis,evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels.Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity.In U87-EGFRvIII cells,CDDP reduced viability modestly(85.2%),C-PC alone decreased viability significantly(51.5%)and induced cell death,but the combination did not further increase apoptosis.Here,C-PC’s pro-apoptotic effects,alone or with CDDP,were also associated with reduced oxidative stress in cells.Conclusion:We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS,suggesting potential for improved therapeutic efficacy with reduced systemic toxicity.Compared to the combination,C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells,underscoring its potential as a standalone therapeutic approach for chemotherapy-resistant glioblastoma subtypes.
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.
文摘Background:Glioblastoma(GBM)remains themost aggressive primary brain tumour in adults,marked by pronounced cellular heterogeneity,diffuse infiltration,and resistance to conventional treatment.In recent years,transcriptomic profiling has provided valuable insights into the molecular mechanisms that govern the progression of glioblastoma.This systematic review aims to synthesise the current literature on dysregulated gene expression in GBM,focusing on gene signatures associatedwith stemness,immunemodulation,extracellularmatrix remodelling,metabolic adaptation,and therapeutic resistance.Methods:We conducted a systematic search of PubMed,The Cancer Genome Atlas(TCGA),Chinese Glioma Genome Atlas(CGGA),and the GlioVis portal for studies published between January 2005 and April 2025,limited to English-language reports.Studies were eligible if they included adult glioblastoma tissue or patient-derived datasets and reported gene-level expression or clinical associations.Reviews,commentaries,and studies on non-GBM gliomas were excluded.Screening followed the PRISMA 2020 checklist,with 410 records initially identified,90 duplicates removed,and 125 studies retained after full-text review.Data were synthesised descriptively,and findings were validated against TCGA/CGGA expression datasets to ensure consistency across cohorts.Results:We categorised recurrently dysregulated genes by their biological function,including transcription factors(SOX2,ZEB2),growth factor receptors(EGFR,PDGFRA),immune-related markers(PD-L1,TAP1,B2M),extracellular matrix regulators(MMP2,LAMC1,HAS2),and metabolic genes(SLC7A11,PRMT5,NRF2).For each group,we examine the functional consequences of transcriptional alterations and their role in driving key glioblastoma phenotypes,including angiogenesis,immunosuppression,invasiveness,and recurrence.Conclusion:We further discuss the prognostic implications of these gene signatures and evaluate their potential utility in precisionmedicine,including current clinical trials that target molecular pathways identified through transcriptomic data.This review highlights the power of gene expression profiling to stratify glioblastoma subtypes and improve personalised therapeutic strategies.
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.
基金support from the National Natural Science Foundation of China(Grant Nos.:82272751 and 82202958)the Natural Science Foundation of Shandong,China(Grant No.:ZR2021LSW002)+6 种基金the Science and Technology Program of Jinan,China(Grant Nos.:202225019 and 202225013)to Man Huthe Shandong Postdoctoral Innovation Program,China(Grant No.:SDCX-ZG-202302011)Beijing Science and Technology Innovation Medical Development Foundation,China(Grant No.:KC2023-JX-0288-BQ26)to Yong Wangthe Natural Science Foundation of China(Grant No.:NSFC82303676)the Natural Science Foundation of Shandong(Grant No.:ZR2023QH208)the China Postdoctoral Science Foundation(Grant No.:2023M732125)the Taishan Scholar Project Special Fund(Grant No.:tsqn202312368)to Kewen He.
文摘Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography(PET/CT)remains limited.This investigation involved the synthesis of[18F]AlF-NOTA-PCP2,which is a novel peptide-based radiolabeled tracer that targets PD-L1,and evaluated its imaging capabilities in orthotopic glioblastoma(GBM)models.Using this tracer,we could noninvasively monitor radiation-induced PD-L1 changes in GBM.[18F]AlF-NOTA-PCP2 exhibited high radiochemical purity(>95%)and stability up to 4 h after synthesis.It demonstrated specific,high-affinity binding to PD-L1 in vitro and in vivo,with a dissociation constant of 0.24 nM.PET/CT imaging,integrated with contrast-enhanced magnetic resonance imaging,revealed significant accumulation of[18F]AlF-NOTA-PCP2 in orthotopic tumors,correlating with blood-brain barrier disruption.After radiotherapy(15 Gy),[18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51%±0.73%to 12.04%±1.43%,indicating enhanced PD-L1 expression consistent with immunohistochemistry findings.Fractionated radiation(5 Gy×3)further amplified PD-L1 upregulation(13.9%±1.54%ID/cc)compared with a single dose(11.48%±1.05%ID/cc).Taken together,[18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.
基金supported by the National Natural Science Foundation of China(No.82001243).
文摘Objectives:Glioblastoma is a prevalent malignant brain tumor,and the actions of the long non-coding RNA HOXA10-AS in its invasion and migration remain unclear.Here,the function of HOXA10-AS in glioblastoma cell invasion and migration and associated mechanisms were investigated.Methods:HOXA10-AS was knocked down in glioblastoma cells,and Transwell and wound healing assays were conducted to elucidate its impacts on cell invasion and migration.Western blotting and quantitative reverse transcription polymerase chain reaction(qRTPCR)assessed HOXA10-AS’s impact on the epithelial-mesenchymal transition(EMT).Microarray analysis identified differentially expressed genes,complemented by bioinformatics approaches to explore potentialmolecular participants and pathways.Rescue experiments validated our findings.Results:HOXA10-AS knockdown significantly inhibits glioblastoma cell migration,invasion,and the EMT process.Specifically,HOXA10-AS siRNA transfection significantly reduced the migratory capacity of A172 cells by 50.5%and U251 cells by 61.4%,as well as their invasive capacities by 33.8%and 58.5%,respectively(all p<0.05).HOXA10-AS acts as anmiR-99a-3p sponge,and pathway analysis identified processes linked to tumorigenesis andmetastasis,alongwith nine hub genes.HOXA10-AS upregulates the expression of integrin subunit beta 5(ITGB5)through a competing endogenous RNAmechanism.Thereduced tumorigenic behavior of glioblastoma cells due toHOXA10-AS knockdown can be rescued by ITGB5 overexpression ormiR-99a-3p inhibitor.Conclusion:These results indicate thatHOXA10-AS promotes tumorigenic behavior in glioblastoma cells by regulating the EMT-like process and functioning as an miR-99a-3p sponge to modulate ITGB5 levels,providing insights into glioblastoma development and potential therapeutic targets.
文摘Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A recent study published in Nature by Faust Akl and colleagues begins to lift the veil on this mystery,uncovering a previously unknown mechanism of immune evasion in GBM[3].
