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: 8690792
• 负责人: Anita Borton Hjelmeland
• 金额: $ 22.96万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690792
• 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; chemoradiation; 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

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.

项目总结

项目成果

Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.

• DOI: 10.1101/gad.235515.113
• 发表时间: 2014-05-15
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Yan K;Wu Q;Yan DH;Lee CH;Rahim N;Tritschler I;DeVecchio J;Kalady MF;Hjelmeland AB;Rich JN
• 通讯作者: Rich JN

Development of a Sox2 reporter system modeling cellular heterogeneity in glioma.

• DOI: 10.1093/neuonc/nou320
• 发表时间: 2015-03
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Kevin Stoltz;M. Sinyuk;J. Hale;Qiulian Wu;B. Otvos;Kiera Walker;A. Vasanji;J. Rich;A. Hjelmeland;J. Lathia

Method for Efficient Transduction of Cancer Stem Cells.

癌症干细胞的有效转导方法。

• DOI: 10.14343/jcscr.2014.2e1008
• 发表时间: 2014
• 期刊: Journal of cancer stem cell research
• 作者: Walker,Kiera;Hjelmeland,Anita
• 通讯作者: Hjelmeland,Anita