The cancer stem cell (CSC) hypothesis is predicated on the idea that not all cells have equal proliferative potential and that, in brain tumors, the cells with the greatest ability to proliferate and form new tumors have phenotypic and functional properties similar to normal stem cells (NSCs). Over the past few years, multiple investigators have shown that CSCs isolated from human glial cell tumors (gliomas and ependymomas) undergo self-renewal and multi-lineage cell differentiation, similar to normal NSCs. In addition, CSCs from these glial tumors when implanted into rodent brains generate tumors histologically identical to the parental tumors, suggesting that these stem cells can fully recapitulate the neoplastic phenotype in vivo. While these seminal studies clearly highlight the central role of stem cells in brain tumor formation, they also evoke important questions regarding the nature of the CSC and its relationship to the normal NSC. Recent evidence in our laboratory and others has raised the possibility that low- grade gliomas (pilocytic astrocytoma; PA) and ependymomas may arise from central nervous system (CNS) region-specific progenitors, based on the presence of distinct CNS region-specific molecular signatures. These findings suggest that stem cells may exist within specific CNS regions that each harbor different biological properties relevant to glial cell differentiation and glial tumorigenesis. In this regard, NSCs isolated from different mouse and human embryonic brain regions have been shown to display intrinsic differences in self-renewal, proliferation, and neurogenesis in vitro and in vivo. Moreover, tumor location is an independent prognostic factor for survival in children with astrocytoma. We hypothesize that the biological properties of glial cells and glial neoplasms are defined by unique genetic programs intrinsic to NSCs originating from different brain regions and that these differences dictate the impact of specific cancer-associated genetic changes on NSC self-renewal and differentiation relevant to glial tumor formation and growth. In this proposal, we plan to define the biological properties of NSCs from different brain locations and to determine the impact of one specific glioma-associated genetic change on brain region NSC biological properties. This study will provide new insights into the spectrum of NSC subtypes in the brain and their role in glial cell differentiation and glial tumor formation. The studies outlined in this proposal are focused on the understanding the intrinsic differences of NSCs from different brain locations and the impact of specific glial tumor- causing genetic changes on NSC properties relevant to glial tumor formation. ? ? ? ?
