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
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
Objectives:Glioblastoma multiforme(GBM)is a highly aggressive brain tumor characterized by extensive transcriptional and epigenetic dysregulation.Brother of the Regulator of Imprinted Sites(BORIS/CTCFL)has been implic...Objectives:Glioblastoma multiforme(GBM)is a highly aggressive brain tumor characterized by extensive transcriptional and epigenetic dysregulation.Brother of the Regulator of Imprinted Sites(BORIS/CTCFL)has been implicated in oncogenic transcriptional programs in several cancers,but its role in GBM remains poorly defined.This study aimed to characterize BORIS-associated transcriptional programs in GBM and to assess their functional relevance using integrative computational and experimental approaches.Methods:Transcriptomic data from The Cancer Genome Atlas(TCGA)-GBM and Genotype-Tissue Expression(GTex)brain cortex were analyzed following batch correction,differential expression analysis,and gene ontology enrichment.TCGA-GBM samples were stratified into BORIS-high and BORIS-low expression quartiles to identify BORIS-associated gene signatures.BORIS chromatin occupancy was examined by Chromatin immunoprecipitation combined with sequencing(ChIP-seq)in U87MG cells,followed by functional annotation of BORIS-bound genes.Experimental validation included BORIS overexpression,RT-qPCR,immunoblotting,ChIP-qPCR,and functional assays assessing proliferation,clonogenic survival,and migration.Results:BORIS was significantly upregulated in GBM compared with normal brain tissue and was associated with transcriptional programs related to development,metabolism,and cell signaling.Quartilebased analysis identified BORIS-associated differentially expressed genes,including CD36 and FBN2.ChIP-seq revealed BORIS binding at promoter-proximal regions,with ChIP-qPCR confirming occupancy at CD36 and FBN2 regulatory regions.BORIS overexpression increased CD36 and FBN2 expression and was associated with reduced proliferation,enhanced clonogenic survival,and increased migratory capacity.Conclusion:These findings indicate that BORIS is associated with transcriptional and phenotypic programs linked to GBM aggressiveness and may represent a candidate for further investigation as a biomarker or therapeutic target in GBM.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
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
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
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.
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 the Secretaría de Ciencia,Humanidades,Tecnología e Innovación(SECIHTI),Fondo Ciencia Básica y de Frontera 2025(CBF-2025-G-97)to E.Soto-Reyes and PRODEP(511/2023-3066-1599)SECIHTI,Fondo de Ciencia de Frontera 2023(CF-2023-G398)to C.Sámano+2 种基金supported by the Departamen to de Ciencias Naturales(DCN),División de Ciencias Naturales e Ingeniería(DCNI),UAM,Unidad Cuajimalpa,through Divisional Project Number 101S243-23 to E.Soto-Reyes and 123 S289-25 to C.Sámanoa master student from Programa de Maestría y Doctorado en Ciencias Bio-químicas,Universidad Nacional Autónoma deMéxico(UNAM)and received a fellowship(CVU number 1184475)fromSecretaría de Ciencia,Humanidades,Tecnología e Innovación(SECIHTI),Mexicoa postdoctoral fellow at the Universidad Autónoma Metropolitana-Cuajimalpa(UAM-C)and received a fellowship(CVU number 588333)from SECIHTI,Mexico.
文摘Objectives:Glioblastoma multiforme(GBM)is a highly aggressive brain tumor characterized by extensive transcriptional and epigenetic dysregulation.Brother of the Regulator of Imprinted Sites(BORIS/CTCFL)has been implicated in oncogenic transcriptional programs in several cancers,but its role in GBM remains poorly defined.This study aimed to characterize BORIS-associated transcriptional programs in GBM and to assess their functional relevance using integrative computational and experimental approaches.Methods:Transcriptomic data from The Cancer Genome Atlas(TCGA)-GBM and Genotype-Tissue Expression(GTex)brain cortex were analyzed following batch correction,differential expression analysis,and gene ontology enrichment.TCGA-GBM samples were stratified into BORIS-high and BORIS-low expression quartiles to identify BORIS-associated gene signatures.BORIS chromatin occupancy was examined by Chromatin immunoprecipitation combined with sequencing(ChIP-seq)in U87MG cells,followed by functional annotation of BORIS-bound genes.Experimental validation included BORIS overexpression,RT-qPCR,immunoblotting,ChIP-qPCR,and functional assays assessing proliferation,clonogenic survival,and migration.Results:BORIS was significantly upregulated in GBM compared with normal brain tissue and was associated with transcriptional programs related to development,metabolism,and cell signaling.Quartilebased analysis identified BORIS-associated differentially expressed genes,including CD36 and FBN2.ChIP-seq revealed BORIS binding at promoter-proximal regions,with ChIP-qPCR confirming occupancy at CD36 and FBN2 regulatory regions.BORIS overexpression increased CD36 and FBN2 expression and was associated with reduced proliferation,enhanced clonogenic survival,and increased migratory capacity.Conclusion:These findings indicate that BORIS is associated with transcriptional and phenotypic programs linked to GBM aggressiveness and may represent a candidate for further investigation as a biomarker or therapeutic target in GBM.
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 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.
