Testing the Cancer Stem Cell Hypothesis: Role of CD133+ Cells as Tumor Stem Cells

描述（由申请人提供）：该项目的目标是深入了解CD133+肿瘤干细胞在人类和小鼠脑肿瘤生长和复发中的作用。越来越多的研究为实体癌中肿瘤干细胞（TSC）的存在提供了支持证据。TSC在操作上被定义为具有肿瘤启动能力和体细胞特征（自我更新和多能性）的肿瘤来源细胞。识别负责肿瘤起始和生长的特定细胞亚群是一个范式转变的想法，它深刻地改变了我们对细胞起源和脑癌治疗方法的看法。在人类脑癌中，肿瘤干细胞是通过细胞表面蛋白CD133的表达来鉴定的。虽然CD133+细胞已被证明是肿瘤启动细胞，但它们是否是肿瘤生长和复发的唯一原因尚不清楚。换句话说，CD133+细胞在肿瘤起始、肿瘤生长和复发中的作用无法用现有的数据明确区分。因此，在实验可及的体内系统中直接和细胞类型特异性消融CD133+细胞是必要的，以检查这些细胞的作用。最近，来自S100-verbB的脑肿瘤干细胞；分离并鉴定了自发发生少突胶质细胞瘤的P53 -/-小鼠。小鼠肿瘤球与人类肿瘤细胞具有相似的分子和细胞特征，包括CD133+细胞的存在。在Aim 1中，将产生一种敲入小鼠，它将允许以暂时可控的方式选择性消融CD133+细胞，并用于检测CD133+细胞在自发性脑肿瘤中的作用。在Aim 2中，将使用来自HOG（人少突胶质细胞瘤）和dao（人髓母细胞瘤）的肿瘤球来检测CD133+细胞在肿瘤发生中的作用。通过结合两种不同的实验系统（自发小鼠模型和培养的人类细胞系），将阐明CD133+细胞在肿瘤发生、生长和复发中的作用，以评估靶向CD133+细胞的潜在治疗益处。

DESCRIPTION (provided by applicant): The goal of this project is to provide insight into the role of CD133+ tumor stem cells in tumor growth and recurrence in human and mouse brain tumors. A growing number of studies provide supporting evidence for the existence of tumor stem cells (TSC) in solid cancers. TSC are operationally defined as tumor derived cells with both tumor initiating capacity and somatic stem cell characteristics (self-renewal and multipotentiality). Identification of a specific subpopulation of cells that is responsible for tumor initiation and growth is a paradigm shifting idea that profoundly changes the way we think about the cellular origin and therapeutic approaches to brain cancer. In human brain cancers, tumor stem cells are identified by their expression of a cell surface protein CD133. While CD133+ cells have been shown to be tumor-initiating cells, it is still unknown whether they are solely responsible for tumor growth and recurrence. In other words, the role of CD133+ cells in tumor initiation vs tumor growth and recurrence cannot be clearly distinguished with existing data. Therefore, direct and cell-type specific ablation of CD133+ cells in an experimentally accessible, in vivo system is necessary to examine the role of these cells. Recently, brain tumor stem cells from S100-verbB;p53-/- mice that spontaneously develop oligodendrogliomas were isolated and characterized. Murine tumorspheres share similar molecular and cellular characteristics with corresponding cells in human cancer, including the presence of CD133+ cells. In Aim 1 a knock-in mouse that will allow selective ablation of CD133+ cells in a temporally controlled manner will be generated, and used to examine the role of CD133+ cells in spontaneous brain tumors. In Aim 2 tumorspheres from HOG (human oligodendroglioma) and DAOY (human medulloblastoma) will be used to examine the role of CD133+ cells in tumorigenesis. By combining two different experimental systems (spontaneous mouse model and cultured human cell lines), the role of CD133+ cells in tumor initiation, growth and recurrence will be elucidated to evaluate the potential therapeutic benefits of targeting CD133+ cells.