A20 Promotes Glioma Stem Cell Mediated Tumorigenesis

描述(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脑瘤，采用最好的治疗方法，中位生存期只有14个月。对肿瘤细胞亚群的生物学和分子特性的更多了解可能会产生迫切需要的新疗法，这些细胞亚群可以自我更新和重现亲本肿瘤。由于对其本质认识的不断发展，这些肿瘤干细胞仍然存在争议：然而，一些报告表明，胶质母细胞瘤含有肿瘤干细胞，这些胶质瘤干细胞有助于治疗抵抗和肿瘤血管生成。我们现在证明细胞存活调节因子A20/肿瘤坏死因子是一种诱导蛋白3，是胶质瘤干细胞的靶点，有助于胶质瘤的生长。虽然关于A20在脑肿瘤中的表达和功能的数据非常有限，而且往往相互矛盾，但我们发现，与非干细胞胶质瘤细胞相比，GSCs持续表达高水平的A20。靶向A20在GSCs中的表达减少了它们的生长，伴随着细胞周期停滞的增加，细胞凋亡的增加和自我更新的减少。靶向GSCs中的A20增加了携带人脑胶质瘤异种移植瘤的小鼠的存活率，对胶质瘤表达数据库的分析表明，A20mRNA的增加与胶质瘤患者存活率较低相关。基于这一背景，我们假设A20促进了胶质瘤的生长和复发，部分原因是维持了肿瘤干细胞的表型。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，以努力确定胶质瘤患者治疗的新靶点。 公共卫生相关性：在一些癌症中，称为癌症干细胞的肿瘤细胞亚组分可能有助于肿瘤的生长和复发。我们的研究发现，A20或肿瘤坏死因子α诱导蛋白3(TNFAIP3)是胶质瘤中一种新的癌症干细胞靶点，与患者生存不良有关。在动物模型中，靶向A20降低了胶质瘤干细胞的存活率，减少了胶质瘤的形成，这表明抗A20治疗可能对胶质瘤患者有利。

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.