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

测试癌症干细胞假说：CD133细胞作为肿瘤干细胞的作用

• 批准号: 7385332
• 负责人: KYUSON YUN
• 金额: $ 18.92万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385332
• 关键词: Ablation; Animal Model; Brain Neoplasms; Cancer cell line; Cell Surface Proteins; Cells; Characteristics; Complement; Cultured Cells; Cultured Tumor Cells; Data; Ganciclovir; Genetically Engineered Mouse; Genotype; Goals; Growth; Human; Human Cell Line; Knock-in Mouse; Malignant Neoplasms; Malignant neoplasm of brain; Molecular; Mus; Neoplasm Transplantation; Numbers; Phenotype; Primary Neoplasm; Reagent; Recurrence; Role; Serum; Solid; Stem cells; System; Testing; Therapeutic; Thinking; Tumor Stem Cells; Tumor-Derived; Xenograft procedure; cancer stem cell; cell type; genetic manipulation; in vivo; insight; medulloblastoma; mouse model; neoplastic cell; nerve stem cell; oligodendroglioma; promoter; self-renewal; tumor; tumor growth; tumor initiation; tumorigenesis

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.

描述（由申请人提供）：本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中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起始能力和体干细胞特性（自我更新和多潜能性）的肿瘤源性细胞。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脑癌细胞起源和治疗方法的看法。在人类脑癌中，肿瘤干细胞通过其细胞表面蛋白CD133的表达来鉴定。虽然CD133+细胞已被证明是肿瘤起始细胞，但仍不清楚它们是否仅负责肿瘤生长和复发。换句话说，CD133+细胞在肿瘤起始与肿瘤生长和复发中的作用不能用现有数据清楚区分。因此，直接和细胞类型特异性消融的CD133+细胞在实验上可访问的，在体内系统是必要的，以检查这些细胞的作用。最近，从自发发展少突胶质细胞瘤的S100-verbB; p53-/-小鼠的脑肿瘤干细胞被分离和表征。鼠肿瘤球与人类癌症中的相应细胞具有相似的分子和细胞特征，包括CD133+细胞的存在。在目标1中，将产生允许以时间控制方式选择性消融CD 133+细胞的敲入小鼠，并用于检查CD 133+细胞在自发性脑肿瘤中的作用。在目的2中，将使用来自HOG（人少突胶质细胞瘤）和DAOY（人髓母细胞瘤）的肿瘤球来检查CD 133+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。