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

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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.