A20 Promotes Glioma Stem Cell Mediated Tumorigenesis

A20 促进神经胶质瘤干细胞介导的肿瘤发生

基本信息

批准号：
8288833
负责人：
Anita Borton Hjelmeland
金额：
$ 25.28万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288833
关键词：
Adjuvant Adult Animal Model Apoptosis Apoptosis Inhibitor Apoptotic BIRC5 gene Binding Biological Brain Neoplasms Cell Cycle Arrest Cell Death Cell Survival Cells DNA Damage DNA damage checkpoint Data Databases Endothelial Cells Excision Gene Cluster Gene Targeting Glioblastoma Glioma Growth Human Hypoxia Link Maintenance Malignant Neoplasms Mediating Messenger RNA Microarray Analysis Modeling Molecular Mus Nature Operative Surgical Procedures Patients Pattern Phenotype Phosphorylation Primary Brain Neoplasms Property Proteins Radiation Radiation Induced DNA Damage Recurrence Reporting Resistance Response Elements Role Signal Pathway Signal Transduction Stem cells TNF gene Therapeutic Therapeutic Studies Transcriptional Activation Tumor Angiogenesis Tumor Necrosis Factor-alpha Vascular Endothelial Growth Factors Xenograft procedure angiogenesis bHLH-PAS factor HLF base cancer stem cell cell growth regulation chemotherapy genetic manipulation inhibitor/antagonist neoplastic cell novel promoter response self-renewal small hairpin RNA stem cell biology temozolomide transcription factor tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY Glioblastomas are the most common and aggressive primary brain tumor in adults, with a median survival of only fourteen months with the best available treatments. Much needed novel therapies may arise from increased appreciation of the biological and molecular properties of subset of tumor cells which can self-renew and recapitulate the parental tumor. These cancer stem cells remain controversial due to the evolving understanding of their nature: however, a number of reports have demonstrated that glioblastomas contain cancer stem cells and that these glioma stem cells contribute to therapeutic resistance and tumor angiogenesis. We now demonstrate that the cell survival regulator A20/Tumor Necrosis Factor a Inducible Protein 3 is a glioma stem cell target which contributes to glioma growth. Although very limited and often contradictory data exists regarding the expression and function of A20 in brain tumors, we find that GSCs consistently express elevated levels of A20 in comparison to non-stem glioma cells. Targeting the expression of A20 in GSCs reduces their growth in association with increased cell cycle arrest, elevated apoptosis, and decreased self-renewal. Targeting A20 in GSCs increased the survival of mice bearing human glioma xenografts, and analysis of a glioma expression database indicates that increased A20 mRNA correlates with poor glioma patient survival. Based on this background, we hypothesize that A20 promotes glioma growth and recurrence due, in part, to maintenance of a cancer stem cell phenotype. We propose to elucidate the molecular and biological role of A20 in glioma stem cell biology in an effort to determine novel targets for glioma patient therapies.

项目概要胶质母细胞瘤是成人中最常见和最具侵袭性的原发性脑肿瘤，采用现有最佳治疗方法，中位生存期仅为十四个月。很多所需的新疗法可能会因对生物学和生物学的认识的增加而产生。肿瘤细胞亚群的分子特性，可以自我更新并概括亲本肿瘤。由于不断进化，这些癌症干细胞仍然存在争议了解其性质：然而，一些报告表明胶质母细胞瘤含有癌症干细胞，这些胶质瘤干细胞有助于治疗耐药性和肿瘤血管生成。我们现在证明细胞生存调节因子 A20/肿瘤坏死因子 a 诱导蛋白 3 是神经胶质瘤干细胞有助于神经胶质瘤生长的目标。尽管非常有限且常常矛盾存在关于 A20 在脑肿瘤中表达和功能的数据，我们发现与非干细胞胶质瘤相比，GSC 始终表达升高的 A20 水平细胞。靶向 GSC 中 A20 的表达会降低其生长，并与以下因素相关：细胞周期停滞增加，细胞凋亡增加，自我更新减少。瞄准 GSC 中的 A20 增加了携带人类神经胶质瘤异种移植物的小鼠的存活率，并且神经胶质瘤表达数据库的分析表明，A20 mRNA 的增加与神经胶质瘤患者的生存率很差。基于此背景，我们假设 A20 促进神经胶质瘤生长和复发，部分原因是维持癌干细胞表型。我们建议阐明 A20 在以下方面的分子和生物学作用：神经胶质瘤干细胞生物学，努力确定神经胶质瘤患者的新靶点疗法。