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
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
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
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
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
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
Objective The systemic immune-inflammation index(SII)has recently attracted significant interest as a new biomarker for predicting the prognosis of patients with glioblastoma(GBM).However,the predictive significance o...Objective The systemic immune-inflammation index(SII)has recently attracted significant interest as a new biomarker for predicting the prognosis of patients with glioblastoma(GBM).However,the predictive significance of it is still a subject of debate.This study intended to assess the clinical effectiveness of the SII in GBM and establish a nomogram.Methods Receiver operating characteristic(ROC)curves were utilized to determine the optimal cut-off values of the SII.Kaplan–Meier(KM)survival curves were used to analyze the median overall survival(OS).Cox regression analysis was carried out to evaluate the associations between OS and different clinical factors.Based on the SII and clinical characteristics,a nomogram was constructed,and its value in clinical application was evaluated by means of decision curve analysis.Results The optimal SII cut-off value was 610.13.KM analysis revealed that GBM patients with higher SII values had shorter OS(15.0 vs.34.0 months,P=0.044).Multivariate analysis demonstrated that a high SII was an independent predictor of poor outcome in GBM(HR=1.79,P=0.029).The nomogram incorporating the preoperative SII showed good predictive accuracy for GBM patient prognosis(C-index=0.691).Conclusions The SII is an independent predictive indicator for GBM.Patients with elevated SII levels tend to have a poorer prognosis.A nomogram combining the SII with clinical and molecular pathological features can assist clinicians in assessing the risk of death in GBM patients,providing a basis for individualized treatment decisions.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
Background:To date,there is no effective cure for the highly malignant brain tumor glioblastoma(GBM).GBM is the most common,aggressive central nervous system tumor(CNS).It commonly originates in glial cells such as mi...Background:To date,there is no effective cure for the highly malignant brain tumor glioblastoma(GBM).GBM is the most common,aggressive central nervous system tumor(CNS).It commonly originates in glial cells such as microglia,oligodendroglia,astrocytes,or subpopulations of cancer stem cells(CSCs).Glucose plays an important role in the,which energy metabolism of normal and cancer cells,but cancer cells exhibit an increased demand for glucose is required for their differentiation and proliferation.The main aim of this study is to explore the anti-cancer efficacy of the ketogenic diet against GBM.Also,this research focuses on the identification of the catalytic action of zinc in epigenetic modulators such as oxyresveratrol and ensures the combinatorial effect in the treatment of GBM.Method:In this study,we have evaluated various parameters to understand the therapeutic efficacy of the treatment groups through in vivo experiments against aggressive brain tumors.Intracerebroventricular experiments were performed to induce the tumor in the animals and estimate the tumor burden and proliferative index.Followed by the Morris water maze,an open field test,and rota rod was performed to evaluate the memory and motor coordination.To understand the glucose,and ketone level modification before and after treatment,the level of glucose and ketone was analyzed.Moreover,the zinc level is assessed using flame atomic absorption spectroscopy.Results:The results suggested that the ketogenic diet has an anti-cancer efficacy against C6-induced GBM cell lines.Also,it exerts a synergistic effect with the epigenetic modulator,oxyresveratrol,and zinc against GBM cell lines.Moreover,the treatment groups improved memory and motor coordination and modified the glucose and ketone levels to reduce the tumor burden and Ki-67 proliferative index.Conclusion:This study revealed the therapeutic effect of the ketogenic diet along with its combination such as oxyresveratrol and zinc against the C6-induced GBM in the Wistar rats.Also,it improved memory and motor coordination and reduced tumor growth.It also modified the glucose and ketone levels in the tumor-induced animal and supported to diminish the tumor burden.展开更多
Glioblastoma(GBM)is a highly infiltrative brain tumor.The treatment of GBM is challenging due to the existence of blood brain barrier,its highly invasive nature,and its heterogeneity.Given the limitations of conventio...Glioblastoma(GBM)is a highly infiltrative brain tumor.The treatment of GBM is challenging due to the existence of blood brain barrier,its highly invasive nature,and its heterogeneity.Given the limitations of conventional therapies,this Perspective explores the development trajectory of implantable devices,highlighting the advantages of current models.With the progression in research,these implantable devices certainly hold promising potential for GBM therapy.展开更多
Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an i...Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.展开更多
Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.Howeve...Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.However,the mechanisms of hypoxia-promoted tumor progression remain elusive.Methods:Alternative splicing of diacylglycerol kinase gamma(DGKG)-Δexon13 was amplified and verified by PCR-Sanger sequencing.The functions of DGKG and DGKG-Δexon13 were analyzed by Cell counting kit-8(CCK-8),Transwell,Matrigeltranswell experiments,and in vivo orthotropic GBM animal models.Transcriptome analyses were done to find out the regulated genes.Results:In this study,we found that a new transcript DGKG-Δexon13 was generated in GBM under hypoxia via alternative splicing.Moreover,the results of CCK-8,Transwell,and Matrigel-transwell experiments showed that the proliferation,migration,and invasion abilities of U87-MG and T98G were decreased after DGKG knockdown.Compared to wild-type DGKG,DGKG-Δexon13 overexpression significantly promoted cellular proliferation,migration,and invasion abilities in GBM.Furthermore,in vivo,orthotropic GBM animal models analysis showed that the tumor volumes were much smaller in the DGKG knockdown group.However,the tumor sizes in the DGKG and DGKG-Δexon13 rescue groups were restored,especially in the DGKG-Δexon13 group.Transcriptome analysis revealed that MORC1,KLHDC7B,ATP1A2,INHBE,TMEM119,and FGD3 were altered significantly when DGKG was knocked down.IL-16,CCN2,and EFNB3 were specifically regulated by DGKG-Δexon13.Conclusions:Our study found that hypoxia-induced alternative splicing transcript DGKG-Δexon13 promotes GBM proliferation and infiltration,which might provide a new potential target for the clinical treatment and diagnosis of GBM.展开更多
Head and neck cutaneous squamous cell carcinoma(HNCSCC)remains underexplored compared to oropharyngeal squamous cell carcinoma,particularly in relation to human papillomavirus(HPV)and molecular markers such as p16 and...Head and neck cutaneous squamous cell carcinoma(HNCSCC)remains underexplored compared to oropharyngeal squamous cell carcinoma,particularly in relation to human papillomavirus(HPV)and molecular markers such as p16 and p53.While p16 is a well-established surrogate for HPV in oropharyngeal cancer,our review highlights its unreliable role in HNCSCC,where positivity is instead associated with recurrence and metastasis.Similarly,p53 illustrates a dual role-wild-type as a genomic safeguard,mutated as an oncogenic driver-complicating prognostication.Methodological considerations,including the limitations of immunohistochemistry for HPV detection,underscore the need for multi-method and molecular validation in future studies.Ultraviolet radiation is posited as a key modifier of p16 function,decoupling expression from tumor suppression.To contextualize these findings,we draw parallels to glioblastoma(GBM),where subclonal evolution,p53 dysfunction,and intratumoral heterogeneity drive relapse despite aggressive multimodal therapies.GBM exemplifies how bulk-level biomarker generalizations often obscure dynamic cellular ecosystems,reinforcing the necessity of single-cell and spatial approaches.Multi-omics integration-encompassing genome,transcriptome,proteome,and tumor microenvironment mapping-coupled with single-cell RNA sequencing and spatial transcriptomics,offers a path forward for resolving subclonal dynamics in both HNCSCC and GBM.These technologies provide the resolution needed to track tumor-immunestromal co-evolution,identify therapy-resistant clones,and anticipate recurrence.We argue for a N-of-1,patient-and cell-centric paradigm that reframes biomarkers not as static surrogates but as dynamic readouts of cancer evolution across time and tissue contexts.Conceptually,we propose kinetic and microenvironmental frameworks(e.g.,“load-and-lock”barriers;dormancy and immunesynapse stabilization)as hypothesis-generating avenues to stall clonal handoffs and improve outcome prediction.Together,these perspectives argue for revised biomarker frameworks in HNCSCC and ethically inclusive,mechanism-anchored studies that bridge discovery with individualized care.By bridging insights from HNCSCC with the lessons of GBM,this review underscores the need for ethically inclusive,mechanistically informed frameworks that integrate subclonal evolution,biomarker re-interpretation,and precision-personalized hybrid models.Such an approach will be essential for advancing from one-size-fits-all strategies to individualized lifetime cancer care.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
Glioblastoma multiforme(GBM)is the most common malignant primary brain tumor with a poor prognosis and limited survival.Patients with GBM have a high demand for palliative care.In our present case,a 21-year-old female...Glioblastoma multiforme(GBM)is the most common malignant primary brain tumor with a poor prognosis and limited survival.Patients with GBM have a high demand for palliative care.In our present case,a 21-year-old female GBM patient received inpatient palliative care services including symptom management,mental and psychological support for the patient,psychosocial and clinical decision support for her family members,and pre-and post-death bereavement management for the family.Furthermore,we provided the family members with comprehensive psychological preparation for the patient's demise and assisted the patient's family throughout the mourning period.The aim of this study is to provide a reference and insights for the clinical implementation of palliative care for patients with malignant brain tumors.展开更多
Among central nervous system-associated malignancies,glioblastoma(GBM)is the most common and has the highest mortality rate.The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently le...Among central nervous system-associated malignancies,glioblastoma(GBM)is the most common and has the highest mortality rate.The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide.In precision medicine,research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity,as well as the refractory nature of GBM toward therapy.Deep understanding of the different molecular expression patterns of GBM subtypes is critical.Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes.The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors.These subtypes also exhibit high plasticity in their regulatory pathways,oncogene expression,tumor microenvironment alterations,and differential responses to standard therapy.Herein,we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype.Furthermore,we review the mesenchymal transition mechanisms of GBM under various regulators.展开更多
Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical int...Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical intervention,and chemotherapy.Unfortunately,the median survival rate remains dishearteningly low at 12–15 months.One of the major obstacles in treating glioblastoma is the recurrence of tumors,making chemotherapy the primary approach for secondary glioma patients.However,the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms.Consequently,considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs.To tackle glioma,numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK.By targeting specific signaling pathways,heterocyclic compounds have demonstrated efficacy in glioma therapeutics.Additionally,key kinases including phosphatidylinositol 3-kinase(PI3K),serine/threonine kinase,cytoplasmic tyrosine kinase(CTK),receptor tyrosine kinase(RTK)and lipid kinase(LK)have been considered for investigation.These pathways play crucial roles in drug effectiveness in glioma treatment.Heterocyclic compounds,encompassing pyrimidine,thiazole,quinazoline,imidazole,indole,acridone,triazine,and other derivatives,have shown promising results in targeting these pathways.As part of this review,we propose exploring novel structures with low toxicity and high potency for glioma treatment.The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier.By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics,we can maximize their therapeutic value and minimize adverse effects.Considering the complex nature of glioblastoma,these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.展开更多
Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to t...Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy.To date,there is still a lack of effective drugs that target VM formation in GBM.In the present study,we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms.Moroidin significantly suppressed cell migration,tube formation,and the expression levels ofα-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations.The RNA sequencing data suggested the involvement of the epithelialmesenchymal transition(EMT)pathway in the mechanism of moroidin.Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells.Moreover,moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase(p-ERK)and inhibited the activation of β-catenin.Finally,we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT.Therefore,our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.展开更多
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.
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.
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.
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funded by National Natural Science Foundation of China,grant number 82203007.
文摘Objective The systemic immune-inflammation index(SII)has recently attracted significant interest as a new biomarker for predicting the prognosis of patients with glioblastoma(GBM).However,the predictive significance of it is still a subject of debate.This study intended to assess the clinical effectiveness of the SII in GBM and establish a nomogram.Methods Receiver operating characteristic(ROC)curves were utilized to determine the optimal cut-off values of the SII.Kaplan–Meier(KM)survival curves were used to analyze the median overall survival(OS).Cox regression analysis was carried out to evaluate the associations between OS and different clinical factors.Based on the SII and clinical characteristics,a nomogram was constructed,and its value in clinical application was evaluated by means of decision curve analysis.Results The optimal SII cut-off value was 610.13.KM analysis revealed that GBM patients with higher SII values had shorter OS(15.0 vs.34.0 months,P=0.044).Multivariate analysis demonstrated that a high SII was an independent predictor of poor outcome in GBM(HR=1.79,P=0.029).The nomogram incorporating the preoperative SII showed good predictive accuracy for GBM patient prognosis(C-index=0.691).Conclusions The SII is an independent predictive indicator for GBM.Patients with elevated SII levels tend to have a poorer prognosis.A nomogram combining the SII with clinical and molecular pathological features can assist clinicians in assessing the risk of death in GBM patients,providing a basis for individualized treatment decisions.
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].
文摘Background:To date,there is no effective cure for the highly malignant brain tumor glioblastoma(GBM).GBM is the most common,aggressive central nervous system tumor(CNS).It commonly originates in glial cells such as microglia,oligodendroglia,astrocytes,or subpopulations of cancer stem cells(CSCs).Glucose plays an important role in the,which energy metabolism of normal and cancer cells,but cancer cells exhibit an increased demand for glucose is required for their differentiation and proliferation.The main aim of this study is to explore the anti-cancer efficacy of the ketogenic diet against GBM.Also,this research focuses on the identification of the catalytic action of zinc in epigenetic modulators such as oxyresveratrol and ensures the combinatorial effect in the treatment of GBM.Method:In this study,we have evaluated various parameters to understand the therapeutic efficacy of the treatment groups through in vivo experiments against aggressive brain tumors.Intracerebroventricular experiments were performed to induce the tumor in the animals and estimate the tumor burden and proliferative index.Followed by the Morris water maze,an open field test,and rota rod was performed to evaluate the memory and motor coordination.To understand the glucose,and ketone level modification before and after treatment,the level of glucose and ketone was analyzed.Moreover,the zinc level is assessed using flame atomic absorption spectroscopy.Results:The results suggested that the ketogenic diet has an anti-cancer efficacy against C6-induced GBM cell lines.Also,it exerts a synergistic effect with the epigenetic modulator,oxyresveratrol,and zinc against GBM cell lines.Moreover,the treatment groups improved memory and motor coordination and modified the glucose and ketone levels to reduce the tumor burden and Ki-67 proliferative index.Conclusion:This study revealed the therapeutic effect of the ketogenic diet along with its combination such as oxyresveratrol and zinc against the C6-induced GBM in the Wistar rats.Also,it improved memory and motor coordination and reduced tumor growth.It also modified the glucose and ketone levels in the tumor-induced animal and supported to diminish the tumor burden.
基金financially supported by the National Natural Science Foundation of China(U23A20591 and 52273158).
文摘Glioblastoma(GBM)is a highly infiltrative brain tumor.The treatment of GBM is challenging due to the existence of blood brain barrier,its highly invasive nature,and its heterogeneity.Given the limitations of conventional therapies,this Perspective explores the development trajectory of implantable devices,highlighting the advantages of current models.With the progression in research,these implantable devices certainly hold promising potential for GBM therapy.
基金supported by the National Natural Science Foundation of China(32171131,32371013,82071429,82471274,and 32371181)Shandong Province Natural Science Foundation(2021ZDSYS11,ZR2019ZD31,and ZR2022MC098)the Taishan Scholars Construction Project.
文摘Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
基金funded by Guizhou Province Science and Technology Plan Project Qiankehe Foundation-ZK[2023]General 360,362Science and Technology Fund project of Guizhou Provincial Health Commission(gzwkj-2022-09,gzwkj-2023-035)+1 种基金National Natural Science Foundation Cultivation Project of Guizhou Medical University(21NSFCP14,gyfynsfc-2022-25)The PhD Scientific Research Launch Fund Project of the Affiliated Hospital of Guizhou Medical University(gyfybsky-2022-02).
文摘Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.However,the mechanisms of hypoxia-promoted tumor progression remain elusive.Methods:Alternative splicing of diacylglycerol kinase gamma(DGKG)-Δexon13 was amplified and verified by PCR-Sanger sequencing.The functions of DGKG and DGKG-Δexon13 were analyzed by Cell counting kit-8(CCK-8),Transwell,Matrigeltranswell experiments,and in vivo orthotropic GBM animal models.Transcriptome analyses were done to find out the regulated genes.Results:In this study,we found that a new transcript DGKG-Δexon13 was generated in GBM under hypoxia via alternative splicing.Moreover,the results of CCK-8,Transwell,and Matrigel-transwell experiments showed that the proliferation,migration,and invasion abilities of U87-MG and T98G were decreased after DGKG knockdown.Compared to wild-type DGKG,DGKG-Δexon13 overexpression significantly promoted cellular proliferation,migration,and invasion abilities in GBM.Furthermore,in vivo,orthotropic GBM animal models analysis showed that the tumor volumes were much smaller in the DGKG knockdown group.However,the tumor sizes in the DGKG and DGKG-Δexon13 rescue groups were restored,especially in the DGKG-Δexon13 group.Transcriptome analysis revealed that MORC1,KLHDC7B,ATP1A2,INHBE,TMEM119,and FGD3 were altered significantly when DGKG was knocked down.IL-16,CCN2,and EFNB3 were specifically regulated by DGKG-Δexon13.Conclusions:Our study found that hypoxia-induced alternative splicing transcript DGKG-Δexon13 promotes GBM proliferation and infiltration,which might provide a new potential target for the clinical treatment and diagnosis of GBM.
文摘Head and neck cutaneous squamous cell carcinoma(HNCSCC)remains underexplored compared to oropharyngeal squamous cell carcinoma,particularly in relation to human papillomavirus(HPV)and molecular markers such as p16 and p53.While p16 is a well-established surrogate for HPV in oropharyngeal cancer,our review highlights its unreliable role in HNCSCC,where positivity is instead associated with recurrence and metastasis.Similarly,p53 illustrates a dual role-wild-type as a genomic safeguard,mutated as an oncogenic driver-complicating prognostication.Methodological considerations,including the limitations of immunohistochemistry for HPV detection,underscore the need for multi-method and molecular validation in future studies.Ultraviolet radiation is posited as a key modifier of p16 function,decoupling expression from tumor suppression.To contextualize these findings,we draw parallels to glioblastoma(GBM),where subclonal evolution,p53 dysfunction,and intratumoral heterogeneity drive relapse despite aggressive multimodal therapies.GBM exemplifies how bulk-level biomarker generalizations often obscure dynamic cellular ecosystems,reinforcing the necessity of single-cell and spatial approaches.Multi-omics integration-encompassing genome,transcriptome,proteome,and tumor microenvironment mapping-coupled with single-cell RNA sequencing and spatial transcriptomics,offers a path forward for resolving subclonal dynamics in both HNCSCC and GBM.These technologies provide the resolution needed to track tumor-immunestromal co-evolution,identify therapy-resistant clones,and anticipate recurrence.We argue for a N-of-1,patient-and cell-centric paradigm that reframes biomarkers not as static surrogates but as dynamic readouts of cancer evolution across time and tissue contexts.Conceptually,we propose kinetic and microenvironmental frameworks(e.g.,“load-and-lock”barriers;dormancy and immunesynapse stabilization)as hypothesis-generating avenues to stall clonal handoffs and improve outcome prediction.Together,these perspectives argue for revised biomarker frameworks in HNCSCC and ethically inclusive,mechanism-anchored studies that bridge discovery with individualized care.By bridging insights from HNCSCC with the lessons of GBM,this review underscores the need for ethically inclusive,mechanistically informed frameworks that integrate subclonal evolution,biomarker re-interpretation,and precision-personalized hybrid models.Such an approach will be essential for advancing from one-size-fits-all strategies to individualized lifetime cancer care.
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National High Level Hospital Clinical Research Funding(2022-PUMCH-B-113).
文摘Glioblastoma multiforme(GBM)is the most common malignant primary brain tumor with a poor prognosis and limited survival.Patients with GBM have a high demand for palliative care.In our present case,a 21-year-old female GBM patient received inpatient palliative care services including symptom management,mental and psychological support for the patient,psychosocial and clinical decision support for her family members,and pre-and post-death bereavement management for the family.Furthermore,we provided the family members with comprehensive psychological preparation for the patient's demise and assisted the patient's family throughout the mourning period.The aim of this study is to provide a reference and insights for the clinical implementation of palliative care for patients with malignant brain tumors.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82172660)Hebei Province Graduate Student Innovation Project(Grant No.CXZZBS2023001)Baoding Natural Science Foundation(Grant No.H2272P015).
文摘Among central nervous system-associated malignancies,glioblastoma(GBM)is the most common and has the highest mortality rate.The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide.In precision medicine,research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity,as well as the refractory nature of GBM toward therapy.Deep understanding of the different molecular expression patterns of GBM subtypes is critical.Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes.The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors.These subtypes also exhibit high plasticity in their regulatory pathways,oncogene expression,tumor microenvironment alterations,and differential responses to standard therapy.Herein,we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype.Furthermore,we review the mesenchymal transition mechanisms of GBM under various regulators.
基金The authors are thankful to Dr.Mayur Yergeri and Science and Engineering Research Board(SERB),Government of India,New Delhi,(CRG/2019/001452).
文摘Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical intervention,and chemotherapy.Unfortunately,the median survival rate remains dishearteningly low at 12–15 months.One of the major obstacles in treating glioblastoma is the recurrence of tumors,making chemotherapy the primary approach for secondary glioma patients.However,the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms.Consequently,considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs.To tackle glioma,numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK.By targeting specific signaling pathways,heterocyclic compounds have demonstrated efficacy in glioma therapeutics.Additionally,key kinases including phosphatidylinositol 3-kinase(PI3K),serine/threonine kinase,cytoplasmic tyrosine kinase(CTK),receptor tyrosine kinase(RTK)and lipid kinase(LK)have been considered for investigation.These pathways play crucial roles in drug effectiveness in glioma treatment.Heterocyclic compounds,encompassing pyrimidine,thiazole,quinazoline,imidazole,indole,acridone,triazine,and other derivatives,have shown promising results in targeting these pathways.As part of this review,we propose exploring novel structures with low toxicity and high potency for glioma treatment.The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier.By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics,we can maximize their therapeutic value and minimize adverse effects.Considering the complex nature of glioblastoma,these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.
基金This work was supported by the National Key Research and Development Program of China(Grant No.2022YFE0104800 to Feng Han)the National Natural Science Foundation of China(Grant No.82003764 to Lili Feng)the Project supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.19KJB350001 to Lili Feng).
文摘Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy.To date,there is still a lack of effective drugs that target VM formation in GBM.In the present study,we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms.Moroidin significantly suppressed cell migration,tube formation,and the expression levels ofα-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations.The RNA sequencing data suggested the involvement of the epithelialmesenchymal transition(EMT)pathway in the mechanism of moroidin.Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells.Moreover,moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase(p-ERK)and inhibited the activation of β-catenin.Finally,we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT.Therefore,our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.
