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Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma

《医学前沿（英文）》 2023年 第17卷 第2期   页码 240-262 doi: 10.1007/s11684-022-0936-z

摘要： Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.

关键词： glioma progression     molecular classification     EM/PM subtyping     intratumor heterogeneity    

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Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell

《医学前沿（英文）》 doi: 10.1007/s11684-023-1017-7

摘要： The association of neurogenesis and gliogenesis with glioma remains unclear. By conducting single-cell RNA-seq analyses on 26 gliomas, we reported their classification into primitive oligodendrocyte precursor cell (pri-OPC)-like and radial glia (RG)-like tumors and validated it in a public cohort and TCGA glioma. The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations, and the pri-OPC-like ones were prone to carrying TP53 mutations. Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes, suggesting their distinct immune evasion programs. Furthermore, the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners. Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes. For example, glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes, respectively. Their expression was positively correlated with those of immune checkpoint genes (e.g., LGALS3) and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells. This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.

关键词： single-cell RNA-seq     glioma     radial glia     primitive oligodendrocyte precursor cell     immune escape    

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RGS16 regulated by let-7c-5p promotes glioma progression by activating PI3K-AKT pathway

《医学前沿（英文）》 2023年 第17卷 第1期   页码 143-155 doi: 10.1007/s11684-022-0929-y

摘要： Gliomas are the most common central nervous system tumours; they are highly aggressive and have a poor prognosis. RGS16 belongs to the regulator of G-protein signalling (RGS) protein family, which plays an important role in promoting various cancers, such as breast cancer, pancreatic cancer, and colorectal cancer. Moreover, previous studies confirmed that let-7c-5p, a well-known microRNA, can act as a tumour suppressor to regulate the progression of various tumours by inhibiting the expression of its target genes. However, whether RGS16 can promote the progression of glioma and whether it is regulated by miR let-7c-5p are still unknown. Here, we confirmed that RGS16 is upregulated in glioma tissues and that high expression of RGS16 is associated with poor survival. Ectopic deletion of RGS16 significantly suppressed glioma cell proliferation and migration both in vitro and in vivo. Moreover, RGS16 was validated as a direct target gene of miR let-7c-5p. The overexpression of miR let-7c-5p obviously downregulated the expression of RGS16, and knocking down miR let-7c-5p had the opposite effect. Thus, we suggest that the suppression of RGS16 by miR let-7c-5p can promote glioma progression and may serve as a potential prognostic biomarker and therapeutic target in glioma.

关键词： RGS16     let-7c-5p     glioma     proliferation     migration    

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Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and

Zhaoshi Bao, Yongzhi Wang, Qiangwei Wang, Shengyu Fang, Xia Shan, Jiguang Wang, Tao Jiang

《医学前沿（英文）》 2021年 第15卷 第4期   页码 551-561 doi: 10.1007/s11684-020-0760-2

摘要： Glioma is the most common lethal tumor of the human brain. The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months. The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas. Unlike primary glioblastoma that usually develop in the elderly, secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5–10 years from the time of diagnosis. Based on various evolutional trajectories brought on by clonal and subclonal alterations, the evolution patterns of glioma vary according to different theories. Some important features distinguish the normal brain from other tissues, e.g., the composition of the microenvironment around the tumor cells, the presence of the blood-brain barrier, and others. The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer. Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment. However, the detailed reasons for the progression and recurrence of glioma remain controversial. In this review, we introduce the different mechanisms involved in glioma progression, including tumor heterogeneity, the tumor microenvironment and drug resistance, and their pre-clinical implements in clinical trials. This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.

关键词： glioma     evolution mechanism     strategies     tumor heterogeneity     secondary glioma    

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Construction of 6HRE-GFAP-Baxα system specific for glioma gene therapy

TIAN Yongji, LI Guilin, GAO Jun, WANG Renzhi, KONG Yanguo, ZHANG Zhenxing, LI Shifang, TIAN Shiqiang, DOU Wanchen, ZHANG Bo

《医学前沿（英文）》 2007年 第1卷 第1期   页码 49-53 doi: 10.1007/s11684-007-0010-x

摘要： The aim of this paper is to construct a specific and high-performance gene therapy system for glioma. We constructed a combined promoter 6HRE-GFAP (Hypoxia Responsive Element, Glial Fibrillary Acidic Protein) by gene recombination techniques according to the hypoxia microenvironment in glioma and tested its efficacy and specificity in cultured cells, and then constructed GFAP-Baxα gene expressing system and determined its promoting of apoptosis in glioma cells. Our primary results showed that in U251 and BT325 cell lines, the activity of GFAP promoter was 16.40 and 4.73-fold of the promoter of hTERT (Human Telomerase Reverse Transcriptase), respectively. The activities of 6HRE-GFAP-promoter increased by 3.08 and 1.30-fold under 2% O condition compared with those under 18% O condition, while under 0.2% O condition increased by 8.90 and 2.69-fold, respectively. The glioma cells showed typical apoptotic signs 90 hours after the transient transfection of GFAP-Baxα. In these primary experiments, it showed that 6HRE-GFAPBaxα system could promote glioma cell apoptosis. It was specific and effective for glioma gene therapy.

关键词： GFAP-Baxα     BT325     Fibrillary     apoptotic     specificity    

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Progress on molecular biomarkers and classification of malignant gliomas

null

《医学前沿（英文）》 2013年 第7卷 第2期   页码 150-156 doi: 10.1007/s11684-013-0267-1

摘要：

Gliomas are the most common primary intracranial tumors in adults. Anaplastic gliomas (WHO grade III) and glioblastomas (WHO grade IV) represent the major groups of malignant gliomas in the brain. Several diagnostic, predictive, and prognostic biomarkers for malignant gliomas have been reported over the last few decades, and these markers have made great contributions to the accuracy of diagnosis, therapeutic decision making, and prognosis of patients. However, heterogeneity in patient outcomes may still be observed, which highlights the insufficiency of a classification system based purely on histopathology. Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment. In this review, we summarize three distinctive biomarkers, three most commonly altered pathways, and three classifications based on microarray data in malignant gliomas.

关键词： malignant glioma     molecular biomarker     IDH1     MGMT     molecular classification    

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胶质瘤细胞系摄取BPA的实验研究

杨磊,王潇,隋丽,孔福全,郝小娟,郑洁莹,马南茹,崔素珍,刘权卫,赵葵

《中国工程科学》 2012年 第14卷 第8期   页码 85-90

摘要：

目的：探讨BPA（2,2-双(4-羟基苯基)丙烷，Bisphenol A）浓度和温度对胶质瘤细胞系摄取和析出10B的影响。方法：将C6和U251两种胶质瘤细胞系，及大鼠正常脑胶质细胞培养在含不同浓度BPA（10B浓度分别为20、40、60、80、100 μg/mL）的培养基中24 h后，采用感应耦合等离子体原子发射光谱（ICP-AES）法测定细胞内硼的含量；将C6细胞培养在含不同浓度BPA的培养基中培养24 h后，更换为不含10B培养基，在不同温度条件（4、25、37 ℃）下继续培养，并分别于换液后的1、2、3 h，用ICP-AES方法检测细胞内的硼含量。结果：细胞内硼浓度随培养基中BPA浓度的增加而增高，胶质瘤细胞内10B浓度约为正常胶质细胞的2.2倍；温度越高，细胞内硼析出速度越快。结论：BPA对胶质瘤细胞系具有一定亲和力；细胞对10B的析出速率具有温度依赖性。

关键词： 硼中子俘获疗法     BPA     胶质瘤细胞系     感应耦合等离子体原子发射光谱    

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硼中子俘获治疗人脑胶质母细胞瘤的前景和困惑

周幽心,孙婷,杨伟廉,杜子威

《中国工程科学》 2012年 第14卷 第8期   页码 82-84

摘要：

硼中子俘获疗法是一种可以选择性杀伤肿瘤细胞的放射疗法，其产生的α粒子对临床治疗新诊断和复发的脑胶质母细胞瘤有较好的疗效。发达国家20世纪五六十年代就已进入临床试验，但一直受到硼携带载体和中子源发展的限制。现就其治疗脑胶质母细胞瘤的前景做一综述。

关键词： 硼中子俘获疗法     多形性胶质母细胞瘤     胶质瘤干细胞    

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光纤微针装置中增强对流药物输注的热强化表征 Article

R. Lyle Hood,Rudy T. Andriani,Tobias E. Ecker,John L. Robertson,Christopher G. Rylander

《工程（英文）》 2015年 第1卷 第3期   页码 344-350 doi: 10.15302/J-ENG-2015077

摘要：

增强对流输注 (CED) 是一项颇具前景的技术，其借助压力驱动流来增强输注药物进入细胞间隙的穿透力。为进一步提升CED的药物分布容积，笔者发明了一种可产生局部亚致死热量的光纤微针装置。本文试图在琼脂糖组织模型中对该技术进行定量表征。在15 °C、20 °C、25 °C和30 °C的恒温条件下，染料的输注在质量分数为0.6%的琼脂糖组织模型中进行分析。输注指标通过自定义阴影成像技术和图像处理算法进行定量。利用所获数据构建一个分布容积的经验预测时序模型作为组织模型温度的函数。接下来通过一组概念验证实验来评估液体输注时新型光纤装置产生局部光加热的能力。恒温输注显示温度和分布容积呈正相关，在100 min时，在30 °C恒温条件下体积扩散是在15 °C恒温条件下的7倍。在光加热 (1064 nm，500 mW) 过程中，输注呈现相似的效果：与对照组 (0 mW) 相比，输注体积在4 h时增大了3.5倍。本文的分析和结果为体积扩散的热介导增强提供了特征描述及新思路。

关键词： 近红外激光     热化学疗法     琼脂糖     光加热     微导管     恶性胶质瘤    

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标题 作者 时间 类型 操作

Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma

期刊论文

Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell

期刊论文

RGS16 regulated by let-7c-5p promotes glioma progression by activating PI3K-AKT pathway

期刊论文

Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and

Zhaoshi Bao, Yongzhi Wang, Qiangwei Wang, Shengyu Fang, Xia Shan, Jiguang Wang, Tao Jiang

期刊论文

Construction of 6HRE-GFAP-Baxα system specific for glioma gene therapy

TIAN Yongji, LI Guilin, GAO Jun, WANG Renzhi, KONG Yanguo, ZHANG Zhenxing, LI Shifang, TIAN Shiqiang, DOU Wanchen, ZHANG Bo

期刊论文

Progress on molecular biomarkers and classification of malignant gliomas

null

期刊论文

胶质瘤细胞系摄取BPA的实验研究

杨磊,王潇,隋丽,孔福全,郝小娟,郑洁莹,马南茹,崔素珍,刘权卫,赵葵

期刊论文

硼中子俘获治疗人脑胶质母细胞瘤的前景和困惑

周幽心,孙婷,杨伟廉,杜子威

期刊论文

光纤微针装置中增强对流药物输注的热强化表征

R. Lyle Hood,Rudy T. Andriani,Tobias E. Ecker,John L. Robertson,Christopher G. Rylander

期刊论文