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Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

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World Journal of stem cells 2024年第5期16卷 604-614页

作者： Edoardo Agosti Marco Zeppieri Mattia Ghidoni Tamara Ius Alessandro Tel Marco Maria Fontanella Pier Paolo Panciani Division of Neurosurgery Department of Medical and Surgical SpecialtiesRadiological Sciences and Public HealthUniversity of BresciaBrescia 25123Italy Department of Ophthalmology University Hospital of UdineUdine 33100Italy Neurosurgery Unit Department of Head-Neck and NeuroScienceUniversity Hospital of UdineUdine 33100Italy Clinic of Maxillofacial Surgery Department of Head-Neck and NeuroScienceUniversity Hospital of UdineUdine 33100Italy

BACKGROUND gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and *** stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and *** studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular *** mechanisms can involve different cellular pathways,most of which have been recently reported in the *** progress,targeted therapeutic approaches lack consensus due to GSCs’high *** To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying *** A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,*** search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text *** them,201 were deemed eligible after excluding 168 for various *** temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma *** analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance *** molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette

关键词： glioma stem cells Chemoresistance Radioresistance Molecular pathways Targeted therapies Systematic review

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glioma stem cells and neural stem cells respond differently to BMP4 signaling

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Cell Regeneration 2022年第1期11卷 374-388页

作者： Xin-Xin Han Chunhui Cai Li-Ming Yu Min Wang Wenhan Yang Dai-Yu Hu Jie Ren Lu-Ying Zhu Jia-Jia Deng Qing-Qing Chen Hua He Zhengliang Gao Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital&School of StomatologyFudan UniversityShanghai 200001China Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center) Tongji University School of MedicineShanghai 200072China Institute of Geriatrics(Shanghai University) Affiliated Nantong Hospital of Shanghai University(The Sixth People’s Hospital of Nantong)School of MedicineShanghai UniversityNantongChina School of Medicine Jiax-ing UniversityJiaxingChina Department of Neurosurgery Changzheng HospitalSecond Military Medical UniversityShanghaiChina Department of Neurosurgery Third Affiliated Hospital of Second Military Medical UniversityShanghaiChina

Malignant glioma is a highly heterogeneous and invasive primary brain tumor characterized by high recurrence rates,resistance to combined therapy,and dismal *** stem cells(GSCs)are likely responsible for tumor progression,resistance to therapy,recurrence,and poor prognosis owing to their high self-renewal and tumorigenic *** a family member of BMP signaling,bone morphogenetic protein4(BMP4)has been reported to induce the differentiation of GSCs and neural stem cells(NSCs).However,the molecular mechanisms underlying the BMP4-mediated effects in these two cell types are *** this study,we treated hGSCs and hNSCs with BMP4 and com-pared the phenotypic and transcriptional changes between these two cell ***,we found that the growth of hGSCs was greatly inhibited by BMP4,but the same treatment only increased the cell size of *** the RNA sequencing results showed that BMP4 treatment evoked significantly transcriptional changes in both hGSCs and hNSCs,the profiles of differentially expressed genes were distinct between the two groups.A gene set that specifically targeted the proliferation and differentiation of hGSCs but not hNSCs was enriched and then validated in hGSC *** results suggested that hGSCs and hNSCs responded differently to BMP4 *** and investigating different responses between hGSCs and hNSCs will benefit finding partner factors working together with BMP4 to further suppress GSCs proliferation and stemness without disturbing NSCs.

关键词： glioma stem cells BMP4 Neural stem cells Cell differentiation Cell proliferation

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The top cited articles on glioma stem cells in Web of Science

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Neural Regeneration Research 2013年第15期8卷 1431-1438页

作者： Fuxin Yi Jun Ma Weimin Ni Rui Chang Wenda Liu Xiubin Han Dongxiao Pan Xingbo Liu Jianwu Qiu Department of Neurosurgery First Affiliated Hospital of Liaoning Medical University

BACKGROUND： glioma is the most common intracranial tumor and has a poor patient prognosis. The presence of brain tumor stem cells was gradually being understood and recognized, which might be beneficial for the treatment of glioma. OBJECTIVE： To use bibliometric indexes to track study focuses on glioma stem cell, and to investigate the relationships among geographic origin, impact factors, and highly cited articles indexed in Web of Science. METHODS： A list of citation classics for glioma stem cells was generated by searching the database of Web of Science-Expanded using the terms ＂glioma stem cell＂ or ＂glioma, stem cell＇＂ or ＂brain tumor stem cell＂. The top 63 cited research articles which were cited more than 100 times were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information on subject categories, country of origin, journals, authors, and source of journals. Inclusive criteria：（1） articles in the field of glioma stem cells which was cited more than 100 times; （2） fundamental research on humans or animals, clinical trials and case reports; （3） research article; （4） year of publication： 1899-2012; and （5） citation database： Science Citation Index-Expanded. Exclusive criteria：（1） articles needing to be manually searched or accessed only by telephone; （2） unpublished articles; and （3） reviews, conference proceedings, as well as corrected papers. RESULTS： Of 2 040 articles published, the 63 top-cited articles were published between 1992 and 2010. The number of citations ranged from 100 to 1 754, with a mean of 280 citations per article. These citation classics came from nineteen countries, of which 46 articles came from the United States. Duke University and University of California, San Francisco led the list of classics with seven papers each. The 63 top-cited articles were published in 28 journals, predominantly Cancer Research and Cancer Cell, followed by Cell stem Cell and Nature. CONCLUSION： Our bib

关键词： Neural regeneration reviews brain glioma stem cells glioma stem cells cancer stem cells literature analysis Web of Science bibliometrics citation neuroregeneration

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Research on human glioma stem cells in China

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Neural Regeneration Research 2017年第11期12卷 1918-1926页

作者： Yao-dong Zhao Quan-bin Zhang Hua Chen Xi-feng Fei Yun-tian Shen Xiao-yan Ji Jia-wei Ma Ai-dong Wang Jun Dong Qing Lan Qiang Huang Department of Neurosurgery and Brain Tumor Research Laboratory Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina Shanghai General Hospital ShanghaiChina Shanghai 10th People's Hospital ShanghaiChina Nanjing First Hospital Nanjing Medical UniversityNanjingJiangsu ProvinceChina Suzhou Kowloon Hospital School of MedicineShanghai Jiao Tong UniversityShanghaiChina

Research on human glioma stem cells began early in the 21st century and since then has become a rapidly growing research field with the number of publications increasing year by year. The research conducted by our diverse group of investigators focused primarily on cell culture techniques, molecular regulation, signaling pathways, cancer treatment, the stem cell microenvironment and the cellular origin and function of glioma stem cells. In particular, we put forward our view that there are inverse or forward transformations among neural stem cells, glial cells and glioma stem cells in glioma tissues under certain conditions. Based on the background of the progress of international research on human glioma stem cells, we aim to share our progress and current findings of human glioma stem cell research in China with colleagues around the world.

关键词： nerve regeneration glioma stem cells China cell culture molecular characteristics cellular origin cell function microenvironment molecular targeted therapy chemotherapy radiotherapy neural regeneration

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Targeting glioma stem cells： enough to terminate gliomagenesis？

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Chinese Medical Journal 2011年第17期124卷 2756-2763页

作者： DONG Jun HUANG Qiang Department of Neurosurgery Second Affiliated Hospital of Suzhou University Suzhou Jiangsu 215004 China

Objective To review the leading roles of glioma stem cells （GSCs） and their sophisticated interactions with other cells in the tissue remodeling process of gliomagenesis. Data sources Published articles about assessing GSCs in tumor initiation, progression, and multiple interactions with other cells in the special microenvironment were selected using PubMed. The search terms were ＂glioma stem cells＂, ＂tumorigenesis＂, and ＂microenvironment＂. Study selection Articles regarding the tissue remodeling of GSCs in gliomagenesis were selected. Results GSCs exhibit enhanced tumor-initiating ability, could reestablish tumor, and were resistant to radiotherapy and chemotherapy. Studying the role of GSCs in gliomagenesis helps to develop targeting therapy against GSCs, which seems to be a cure for gliomas. However, sophisticated interactions between GSCs and their local microenvironment during tumor remodeling, including integrating with partially differentiated tumor cells, GSCs niche, neural stem cells （NSCs）, normal glia, tumor-infiltrating lymphocytes, may obscure the leading role of GSCs during gliomagenesis, and make single targeting therapy unsuccessful. Conclusions Understanding the biological behavious of GSCs and their regulatory mechanisms may directly impact current efforts for more directed therapeutics against the highly aggressive gliomas. For multiple possible sources to turning into GSCs, simply eradicating the existing GSCs is not enough to be a cure for gliomas, blocking the potential sources of GSCs and ameliorating the local tumor inducing/promoting microenvironment should be a reasonable strategy.

关键词： glioma stem cells tumorigenesis microenvironment

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SOX transcription factors and glioma stem cells:Choosing between stemness and differentiation

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World Journal of stem cells 2021年第10期13卷 1417-1445页

作者： Milena Stevanovic Natasa Kovacevic-Grujicic Marija Mojsin Milena Milivojevic Danijela Drakulic Laboratory for Human Molecular Genetics Institute of Molecular Genetics and Genetic EngineeringUniversity of BelgradeBelgrade 11042Serbia Chair Biochemistry and Molecular Biology Faculty of BiologyUniversity of BelgradeBelgrade 11158Serbia Department of Chemical and Biological Sciences Serbian Academy of Sciences and ArtsBelgrade 11000Serbia

Glioblastoma(GBM)is the most common,most aggressive and deadliest brain ***,remarkable progress has been made towards understanding the cellular and molecular biology of *** tumor initiation,progression and relapse as well as resistance to treatments are associated with glioma stem cells(GSCs).GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types,generating a range of distinct cell types within the tumor,leading to cellular *** tumors may contain different subsets of GSCs,and some of them may adopt a quiescent state that protects them against chemotherapy and *** enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties,making them more malignant,able to rapidly *** impact of SOX transcription factors(TFs)on brain tumors has been extensively studied in the last *** all SOX genes are expressed in GBM,and their expression levels are associated with patient prognosis and *** SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC *** fine-tuning of SOX gene expression levels controls the balance between cell stemness and ***,innovative therapies targeting SOX TFs are emerging as promising tools for combatting *** GBM has been a demanding and challenging goal for *** current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient *** approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.

关键词： Glioblastoma SOX transcription factors glioma stem cells stemness Differentiation

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MiR-181b suppresses proliferation of and reduces chemoresistance to temozolomide in U87 glioma stem cells

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The Journal of Biomedical Research 2010年第6期24卷 436-443页

作者： Ping Li Xiaoming Lu Yingyi Wang Lihua Sun Chunfa Qian Wei Yan Ning Liu Yongping You Zhen Fu Department of Neurosurgery the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Neurosurgery the Affiliated Brain Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China

MicroRNAs regulate self renewal and differentiation of cancer stem ***,we sought to identify the expression of miR-181b in glioma stem cells and investigate the biological effect of miR-181b on glioma stem cells in this ***-181b expression was measured by real-time PCR in glioma stem cells isolated from U87 cells by FACS *** miR-181b was overexpressed in U87 glioma stem cells by miR-181b lentiviral expression vector and/or treatment of temozolomide,secondary neurosphere assay,soft agar colony assay and MTT assay were *** with U87 cells,the expression of miR-181b was significantly decreased in U87 glioma stem *** of miR-181b decreased neurosphere formation by U87 glioma stem cells in vitro and suppressed colony formation in soft agar,and the cell growth inhibition rates increased in a time-dependent manner in U87 glioma stem cells infected with miR-181b ***,miR-181b had a synergistic effect on temozolomide-induced inhibition of secondary neurosphere and soft agar colony,and on cell growth inhibition ***-181b functions as a tumor suppressor that suppresses proliferation and reduces chemoresistance to temozolomide in glioma stem cells.

关键词： miR-181b glioma stem cells proliferation chemoresistance

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glioma stem cells and the occurrence of tumor blood vessels

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Discussion of Clinical Cases 2015年第2期2卷 12-22页

作者： Yude Zhu Qiang Huang The Third Affiliated Hospital of Inner Mongolia Medical University HohhotChina

Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of *** median survival time of patients with advanced glioma is only 12 to 18 months due to the characteristics of high aggression,and the therapeutic effect was poor though surgery,chemotherapy,and targeted drug therapy being *** of the presence of heterogeneity and the differentiation disorder,only a small number of glioma cells are the source of tumor growth and metastasis,which are highly resistant to traditional *** are deemed as the“seed”tumor cells as they could get rid of the effect of the treatment and reconstruct the organization of *** are also termed as brain tumor stem cell(BTSC)or glioma stem cells(GSCs)since neural stem cells share similar features with *** data reveal that they are directly related with invasion,angiogenesis,tolerance,chemotherapy,recurrence of *** on the research result by the team,the paper elaborates the characteristics of GSCs and the relationship with the tumor angiogenesis.

关键词： glioma stem cells Tumor blood vessels

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glioma stem cells involved in tumor tissue remodeling in a xenograft model

Glioma stem cells involved in tumor tissue remodeling in a x...

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中华医学会神经外科学分会第九次学术会议

作者：董军兰青黄强苏州大学附属第二医院神经外科

Object Although tissue remodeling plays a crucial role in the tumorigenesis and progression of human gliomas,its mechanisms remain largely *** the current study,the authors investigated the potential role of human gli... 详细信息

关键词： glioma stem cells tissue remodeling

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HIF1α/HIF2α induces glioma cell dedifferentiation into cancer stem cells through Sox2 under hypoxic conditions

HIF1α/HIF2α induces glioma cell dedifferentiation into can...

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第十六届中国医师协会神经外科医师年会

作者： Pan Wang Bin Liao Jinyu Pan Junwei Wang Dewei Zou Lu Zhao Shuanglong Xiong Yangmin Deng Qian Yan Sheng Gong Nan Wu Chongqing Medical University Department of Neurosurgery Chongqing General HospitalUniversity of Chinese Academy of Sciences Department of Oncology Chongqing University Cancer Hospital

Objective:Our last study found that glioma stem-like cells could be induced through dedifferentiation under hypoxic conditions,but the mechanism requires further ***1α and HIF2α are the main molecules involved in the response to hypoxia,and Sox2,as a retroelement,plays an important role in the formation of induced pluripotent stem cells,especially in hypoxic ***,we performed a series of experiments to verify whether HIF1α,HIF2α and Sox2 regulated glioma cells dedifferentiation under hypoxic *** and methods:Spheres formation by single glioma cells were detected and compared CD133 and CD15 expression between normoxic and hypoxic *** HIF1α,HIF2α,Sox2 expression using CGGA database and analyzed the correction of HIF1α,HIF2α and *** knocked out HIF1α,HIF2α and Sox2 in glioma cells and cultured them in hypoxia to detect CD133 and CD15 *** above were implanted into mice brain to analyze tumor volume and survival ***:Newly spheres formed from single glioma cells in 1% O2,but no spheres formed in 21% *** cells in 1% O2 were highly expressed CD133 and CD15 and had a lower apoptosis *** database showed there were HIF1α and HIF2α expression in *** out HIF1α or HIF2α leaded to a decrease of CD133 and CD15 and inhibited spheres formation in ***,tumor volume became smaller after HIF1α or HIF2α knock out with the same temozolomide ***2 was also highly expressed in glioma and there were positive correction between HIF1α/HIF2α and *** were lower Sox2 expression after HIF1α or HIF2α knocked *** Sox2 was knocked out and we found CD133 and CD15 expression was ***,a lower spheres formation rate,higher apoptosis rate,lower tumor formation and longer survival time with the temozolomide treatment were detected for Sox2 knock out ***:In the hypoxic microenvironment,the HIF1α/HIF2α-Sox2 network induced the formation of glioma st

关键词： glioma stem cells dedifferentiation hypoxia HIF1α/HIF2α Sox2

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