Regulation of Asymmetric Cellular Division in Glioma Stem Cells

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见和最恶性的原发性脑肿瘤。最近的研究表明，一小部分肿瘤细胞，称为胶质瘤干细胞（GSC），可能会控制GBM的生物学行为。GSC具有自我更新、多能性和高致瘤性的特性。迄今为止，它们已经通过特异性标志物如CD 133、Sox 2和巢蛋白的表达来鉴定，但负责干细胞样行为的分子机制尚未明确定义，干细胞/非干细胞平衡的调节剂也未明确定义。该提案旨在定义赋予GSC干细胞样品质并丰富其在GBM中存在的分子机制。在黑腹果蝇神经系统中，指导不对称细胞分裂和干细胞样行为的途径已经得到很好的描述，并可能为恶性胶质瘤中干细胞特性和干/非干细胞平衡提供线索。果蝇脑肿瘤（brat）基因产物通过将其分离到注定分化的子细胞中来调节不对称细胞分裂，在子细胞中其功能是抑制Myc。在brat突变体中，不对称分裂和神经分化不会发生，导致大量扩大的幼虫大脑含有高度增殖的未分化的神经母细胞与肿瘤特性。果蝇brat的人类同源物Trim 3在超过25%的GBM中显示等位基因丢失，并且几乎所有GBM的表达都降低。在目前的提案中，我们假设减少Trim 3或其相互作用蛋白的表达，通过有利于不对称细胞分裂的丧失和丰富干细胞区室，在定义人类GSC中的干细胞样特性方面至关重要。我们建议研究Trim 3在人类胶质瘤中的表达，以确定其在人类GBM中的表达是否下调; Trim 3是否在体外和体内调节c-Myc蛋白的表达和活性; Trim 3是否在GBM神经球培养物和GBM切除标本中调节人类的干细胞样性质;遗传和缺氧机制是否在肿瘤进展期间调节Trim 3;以及Trim 3是否调节动物模型中GBM的体内生长特性。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common and most malignant primary brain tumor. Recent studies suggest that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), may govern the biologic behavior of GBM. GSCs have properties of self-renewal, pluripotency and high tumorigenicity. They have thus far been identified by the expression of specific markers, such as CD133, Sox2 and nestin, yet molecular mechanisms responsible for stem-like behavior have not been clearly defined, nor have regulators of the stem/non-stem equilibrium. This proposal aims to define molecular mechanisms that confer stem-like qualities to GSCs and enriches their presence in GBMs. Pathways that direct asymmetric cellular division and stem-like behavior in the Drosophila melanogaster nervous system have been well described and may provide clues to stem cell properties and the stem/non-stem balance in malignant gliomas. The Drosophila brain tumor (brat) gene product regulates asymmetric cell division through its segregation into the daughter cell destined for differentiation, where it functions to translationally repress Myc. In brat mutants, asymmetric division and neural differentiation do not occur, leading to a massively enlarged larval brain containing highly proliferative undifferentiated neuroblastic cells with neoplastic properties. The human homolog of Drosophila brat, Trim3, shows allelic loss in over 25% of GBMs and reduced expression in nearly all. In the current proposal, we hypothesize that reduced expression of Trim3, or its interacting proteins, is critical in defining stem-like properties in human GSCs by favoring a loss of asymmetric cell division and enriching the stem cell compartment. We propose to investigate Trim3 in human gliomas in order to determine if its expression is downregulated in human GBMs; if Trim3 regulates c-Myc protein expression and activity in vitro and in vivo; if Trim3 regulates stem like properties of human in GBM neurosphere cultures and GBM resection specimens; if genetic and hypoxic mechanisms regulate Trim3 during tumor progression; and if Trim3 regulates the in vivo growth properties of GBM in animal models.