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

• 批准号: 8100319
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100319
• 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; public health relevance; response; self-renewal; small hairpin RNA; stem cell biology; temozolomide; transcription factor; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In some cancers, a sub-fraction of tumor cells called cancer stem cells may contribute to tumor growth and recurrence. Our studies identify A20, or Tumor Necrosis Factor Alpha Inducible Protein 3 (TNFAIP3), as a novel cancer stem cell target in glioma linked to poor patient survival. Targeting A20 decreases glioma stem cell survival and reduces glioma formation in animal models, indicating anti-A20 therapies may be beneficial for glioma patients.

描述（由申请人提供）：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，采用最佳治疗方法的中位生存期仅为14个月。对肿瘤细胞亚群的生物学和分子学特性的认识增加可能会产生急需的新疗法，这些肿瘤细胞亚群可以自我更新并重现亲代肿瘤。这些癌症干细胞仍然存在争议，由于其性质的不断发展的理解：然而，一些报告已经证明，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，细胞存活调节因子A20/肿瘤坏死因子a诱导蛋白3是胶质瘤干细胞的目标，有助于胶质瘤的生长。尽管关于A20在脑肿瘤中的表达和功能的数据非常有限且常常相互矛盾，但我们发现，与非干细胞胶质瘤细胞相比，GSC始终表达升高水平的A20。靶向GSC中A20的表达降低了它们的生长，这与细胞周期停滞增加、凋亡增加和自我更新减少有关。靶向GSC中的A20增加了携带人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存活率差相关。基于这一背景，我们假设A20促进胶质瘤生长和复发，部分原因是维持了癌症干细胞表型。我们建议阐明A20在胶质瘤干细胞生物学中的分子和生物学作用，以确定胶质瘤患者治疗的新靶点。 公共卫生相关性：在某些癌症中，称为癌症干细胞的肿瘤细胞亚部分可能有助于肿瘤生长和复发。我们的研究确定了A20或肿瘤坏死因子α诱导蛋白3（TNFAIP 3）作为胶质瘤中与患者生存率低相关的新型癌症干细胞靶点。在动物模型中，靶向A20降低了胶质瘤干细胞的存活率并减少了胶质瘤的形成，这表明抗A20疗法可能对胶质瘤患者有益。