Abstract 4194: Interrogation of glioma ontogeny using mouse models

Abstract Gliomas are a group of primary brain tumours that comprise almost 60% of total human central nervous system (CNS) malignancies. The malignant Grade IV Glioblastoma Multiforme (GBM) being the most common, is associated with a median survival of ∼16mths. Gliomas are recognized as highly heterogeneous tumors, however, the phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of an oncogenic stimuli, thus it is possible that this variability might reflect inherent characteristics of the tumour cell of origin. For several decades it was widely assumed that differentiated glia were the only cells capable of transformation as the adult brain was thought to be mitotically inactive, however demonstration of functional neurogenesis in the adult brain provided new possibilities for the candidate cell of origin of CNS neoplasms. Currently, controversy exits on whether the initial transformed cell is a differentiated astrocyte, progenitor or neural stem cell. Putative Cancer stem cells (CSCs), which have features of normal stem cell (self-renewal, multi-potent differentiation) plus the ability to recapitulate the tumor phenotype in vivo in small numbers, have been identified from a variety of solid human cancers including GBMs. However, it is still to be determined whether the appearance of brain tumor stem cells is the cause or consequence of tumor initiation and progression. Using a novel mouse model we will study the gliomagenic potential of different glial precursors at different developmental stages. Towards this objective, a conditional transgenic system which integrates Cre-Loxp mediated and Tet- regulated expression, will be utilized to drive expression of K-Ras to Nestin, BLBP and GFAP positive cells, which target Neural Stem cells, Radial glial cells and terminally differentiated astrocytes, respectively. Specifically, our interests are in the similarities or differences in the incidence, location, subtype, grade, proliferation, apoptosis and angiogenic status of the expected gliomas that result amongst these different transgenics. All of the transgenics have been derived, and control experiments confirm that expression of Kras is dependent on both Cre excision and Dox administration, as shown by Reverse Transcriptase-PCR and Ras GTP pull-downs. If astroglial progenitors are more gliomagenic, we would expect the Blbp-Cre or Nestin-Cre transgenics to result in increased number, more periventricular and potentially different glioma subtypes. These series of experiments will allow us to determine the gliomagenic potential (incidence, subtype, grade) in mature vs. glial progenitor cell compartments at different developmental time-points. The ability to manipulate GEMs developmentally and spatially will allow us to directly interrogate the ontogeny of gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4194.

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