Glioblastoma(GB)is the most common primary malignant brain tumor of adulthood,and despite optimal safe resection and chemoradiation,it is still lethal.Neuroscience of cancer has shown that neuronal activities,as well ...Glioblastoma(GB)is the most common primary malignant brain tumor of adulthood,and despite optimal safe resection and chemoradiation,it is still lethal.Neuroscience of cancer has shown that neuronal activities,as well as neurotransmitters,play an active role in the glioma microenvironment.This article aims to integrate the existing literature on the role of neurotransmitters and their receptors in glioblastoma,as well as other gliomas,highlighting areas of therapeutic intervention in the neuron-tumor interface.We will describe the neuro–glioma interface,including functional neuron–glioma synapses and activity-dependent tumor growth.We will also discuss major neurotransmitter systems involved in glioma pathobiology:glutamate,gamma aminobutyric acid,acetylcholine,dopamine,serotonin,norepinephrine,and other neurotransmitters.We will highlight that these neurotransmitter systems activate common intracellular signaling pathways that control tumor proliferation,invasion,metabolic reprogramming,immune suppression,therapy resistance,etc.In addition,some reports have found tumor-suppressing effects depending on the context.The involvement of neurotransmitter-driven signaling pathways represents a promising area of clinical potential in glioma pathobiology.In particular,focusing on key neurotransmitter systems with blood–brain barrier-permeable agents like alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA/Xc−)system,Muscarinic acetylcholine receptor M3(CHRM3),dopamine receptor D2,monoamine oxidase A,etc.,may enhance drug-repurposing research as well as development of novel anti–neuron–glioma agents.展开更多
Objectives:Germline variants in cancer predisposition genes have been increasingly recognized in pediatric cancers.However,their spectrum in East Asian children with central nervous system(CNS)tumors remains insuffici...Objectives:Germline variants in cancer predisposition genes have been increasingly recognized in pediatric cancers.However,their spectrum in East Asian children with central nervous system(CNS)tumors remains insufficiently defined.This study investigated the prevalence and clinical significance of pathogenic or likely pathogenic(P/LP)germline mutations in Korean children,adolescents,and young adults(AYAs)with CNS tumors.Methods:We performed targeted next-generation sequencing of 358 cancer-associated genes using peripheral blood DNA from 108 patients.Germline variants were classified according to ACMG/AMP guidelines and curated using ClinVar and relevant literature.Results:Among 108 patients,17(15.7%)carried P/LP germline variants.The median age at diagnosis was 7.7 years(range,1.0–24.0),and 64.7%were male.P/LP variants were most frequent in other CNS tumors(4/11,36.4%),including 2 glioneuronal tumors,1 schwannoma,1 atypical teratoid rhabdoid tumor(ATRT),and gliomas(9/32,28.1%),followed by medulloblastomas(3/31,9.7%).In gliomas,P/LP variants in MLH1,NF1,MUTYH,PALB2,PMS2,FANCM,and TP53 were observed,while medulloblastomas carried alterations in SUFU,BRIP1,and FANCI.SMARCB1 variant was found in ATRT.Among 25 patients with intracranial germ cell tumors,only a single case carried a P/LP germline variant,identified in FANCI.Conclusion:Germline P/LP mutations were identified in 15.7%of Korean children and AYAs with CNS tumors,most commonly in gliomas and other CNS tumors.Our findings highlight the molecular heterogeneity of germline predisposition in CNS tumors and emphasize the importance of germline testing for risk assessment and surveillance.展开更多
目的探究小分子药物WP1066对MYCN扩增型神经母细胞瘤(neuroblastoma,NB)增殖的抑制作用及分子机制。方法从26种获美国食品药品监督管理局(Food and Drug Administration,FDA)批准或处于临床试验阶段的儿童药物中,筛选出对MYCN扩增型NB细...目的探究小分子药物WP1066对MYCN扩增型神经母细胞瘤(neuroblastoma,NB)增殖的抑制作用及分子机制。方法从26种获美国食品药品监督管理局(Food and Drug Administration,FDA)批准或处于临床试验阶段的儿童药物中,筛选出对MYCN扩增型NB细胞SK-N-BE(2)杀伤效果最显著的药物WP1066。使用不同浓度梯度WP1066处理MYCN扩增型NB细胞SK-N-BE(2)、IMR32,MYCN非扩增型NB细胞SH-SY5Y、SK-N-AS,人视网膜上皮细胞hTERT RPE-1,采用CellTiter-Glo、结晶紫染色、克隆形成等实验检测细胞增殖及活力,Caspase3/7试剂盒检测细胞凋亡,Western blotting检测信号转导和转录激活因子3(signal transducer and activator of transcription 3,STAT3)和p-STAT3蛋白水平的表达,实时荧光定量反转录聚合酶链式反应(real-time quantitative reverse transcription polymerase chain reaction,RT-qPCR)检测抗凋亡分子Bcl-2 mRNA水平的表达。结果CellTiter-Glo结果显示,WP1066对MYCN扩增型NB细胞SK-N-BE(2)、IMR32杀伤效果显著(P<0.05),相同浓度下对MYCN非扩增型NB细胞SH-SY5Y、SK-N-AS,人视网膜上皮细胞hTERT RPE-1的影响不显著。结晶紫染色和克隆形成实验也显示出同样的实验结果。Caspase3/7检测细胞凋亡结果显示,WP1066显著促进MYCN扩增型NB细胞SK-N-BE(2)凋亡(P<0.05),但是对MYCN非扩增型NB细胞SH-SY5Y没有显著影响。在机制方面,小分子药物WP1066通过抑制SK-N-BE(2)细胞p-STAT3水平及其下游抗凋亡分子Bcl-2的表达水平(P<0.05),进而抑制NB细胞活力。结论WP1066对MYCN扩增型NB细胞增殖有显著的抑制作用,有望成为MYCN扩增型NB的候选治疗药物。展开更多
基金Funded by the European Union—Next Generation EU—NRPP M6C2—Investment 2.1 Enhancement and Strenghtening of Biomedical Research in the NHS(Cod.ID.PNRR-TR1-2023-12377972 CUP H43C24000520006).
摘要Glioblastoma(GB)is the most common primary malignant brain tumor of adulthood,and despite optimal safe resection and chemoradiation,it is still lethal.Neuroscience of cancer has shown that neuronal activities,as well as neurotransmitters,play an active role in the glioma microenvironment.This article aims to integrate the existing literature on the role of neurotransmitters and their receptors in glioblastoma,as well as other gliomas,highlighting areas of therapeutic intervention in the neuron-tumor interface.We will describe the neuro–glioma interface,including functional neuron–glioma synapses and activity-dependent tumor growth.We will also discuss major neurotransmitter systems involved in glioma pathobiology:glutamate,gamma aminobutyric acid,acetylcholine,dopamine,serotonin,norepinephrine,and other neurotransmitters.We will highlight that these neurotransmitter systems activate common intracellular signaling pathways that control tumor proliferation,invasion,metabolic reprogramming,immune suppression,therapy resistance,etc.In addition,some reports have found tumor-suppressing effects depending on the context.The involvement of neurotransmitter-driven signaling pathways represents a promising area of clinical potential in glioma pathobiology.In particular,focusing on key neurotransmitter systems with blood–brain barrier-permeable agents like alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA/Xc−)system,Muscarinic acetylcholine receptor M3(CHRM3),dopamine receptor D2,monoamine oxidase A,etc.,may enhance drug-repurposing research as well as development of novel anti–neuron–glioma agents.
基金supported by a research grant(No.2110320-1,2,3)from the National Cancer Center,Republic of Korea.The funding organization had no role in the design or conduct of this research.
摘要Objectives:Germline variants in cancer predisposition genes have been increasingly recognized in pediatric cancers.However,their spectrum in East Asian children with central nervous system(CNS)tumors remains insufficiently defined.This study investigated the prevalence and clinical significance of pathogenic or likely pathogenic(P/LP)germline mutations in Korean children,adolescents,and young adults(AYAs)with CNS tumors.Methods:We performed targeted next-generation sequencing of 358 cancer-associated genes using peripheral blood DNA from 108 patients.Germline variants were classified according to ACMG/AMP guidelines and curated using ClinVar and relevant literature.Results:Among 108 patients,17(15.7%)carried P/LP germline variants.The median age at diagnosis was 7.7 years(range,1.0–24.0),and 64.7%were male.P/LP variants were most frequent in other CNS tumors(4/11,36.4%),including 2 glioneuronal tumors,1 schwannoma,1 atypical teratoid rhabdoid tumor(ATRT),and gliomas(9/32,28.1%),followed by medulloblastomas(3/31,9.7%).In gliomas,P/LP variants in MLH1,NF1,MUTYH,PALB2,PMS2,FANCM,and TP53 were observed,while medulloblastomas carried alterations in SUFU,BRIP1,and FANCI.SMARCB1 variant was found in ATRT.Among 25 patients with intracranial germ cell tumors,only a single case carried a P/LP germline variant,identified in FANCI.Conclusion:Germline P/LP mutations were identified in 15.7%of Korean children and AYAs with CNS tumors,most commonly in gliomas and other CNS tumors.Our findings highlight the molecular heterogeneity of germline predisposition in CNS tumors and emphasize the importance of germline testing for risk assessment and surveillance.
摘要目的探究小分子药物WP1066对MYCN扩增型神经母细胞瘤(neuroblastoma,NB)增殖的抑制作用及分子机制。方法从26种获美国食品药品监督管理局(Food and Drug Administration,FDA)批准或处于临床试验阶段的儿童药物中,筛选出对MYCN扩增型NB细胞SK-N-BE(2)杀伤效果最显著的药物WP1066。使用不同浓度梯度WP1066处理MYCN扩增型NB细胞SK-N-BE(2)、IMR32,MYCN非扩增型NB细胞SH-SY5Y、SK-N-AS,人视网膜上皮细胞hTERT RPE-1,采用CellTiter-Glo、结晶紫染色、克隆形成等实验检测细胞增殖及活力,Caspase3/7试剂盒检测细胞凋亡,Western blotting检测信号转导和转录激活因子3(signal transducer and activator of transcription 3,STAT3)和p-STAT3蛋白水平的表达,实时荧光定量反转录聚合酶链式反应(real-time quantitative reverse transcription polymerase chain reaction,RT-qPCR)检测抗凋亡分子Bcl-2 mRNA水平的表达。结果CellTiter-Glo结果显示,WP1066对MYCN扩增型NB细胞SK-N-BE(2)、IMR32杀伤效果显著(P<0.05),相同浓度下对MYCN非扩增型NB细胞SH-SY5Y、SK-N-AS,人视网膜上皮细胞hTERT RPE-1的影响不显著。结晶紫染色和克隆形成实验也显示出同样的实验结果。Caspase3/7检测细胞凋亡结果显示,WP1066显著促进MYCN扩增型NB细胞SK-N-BE(2)凋亡(P<0.05),但是对MYCN非扩增型NB细胞SH-SY5Y没有显著影响。在机制方面,小分子药物WP1066通过抑制SK-N-BE(2)细胞p-STAT3水平及其下游抗凋亡分子Bcl-2的表达水平(P<0.05),进而抑制NB细胞活力。结论WP1066对MYCN扩增型NB细胞增殖有显著的抑制作用,有望成为MYCN扩增型NB的候选治疗药物。