Abstract 3302: Roles of cortical and subventricular GFAP+ astrocytes in initiation of astrocytomas

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Astrocytomas, including glioblastomas (GBM), are characterized by cellular, molecular, and morphological heterogeneity, which raises the question from which cells astrocytomas originate. Research with many different types of cancer has established that tumor initiating cells share molecular characteristics and gene expression signatures with stem cells; however, the origin of glioma initiating cells and their relationship to adult neural stem cells remains unclear. Using conditional, inducible genetically-engineered mouse models (GEMM) with inactivated RB (GFAP-driven transgenic expression of N-terminal SV40 large T mutant (T121), T) and/or PTEN (P) and/or constitutively activated KRAS (R, KRAS(G12D)), we show that tumorigenesis was initiated in both parenchymal GFAP+ astrocytes as well as GFAP+ NSC/progenitor cells in the subventricular zone (SVZ) within two weeks of induction in adult mice. The induced GFAP+ cells proliferated (measured by EDU incorporation) and expressed multiple neural stem cell (NSC) markers such as Sox2, nestin and CD133, which persisted in developing astrocytomas over several months. Primary cortical astrocytes from TRP-/- mice cultured in vitro under NSC conditions displayed self-renewal and multi-lineage differentiation potential and expressed multiple NSC markers. When stereotactically injected in the diencephalon of syngeneic recipient mice, astrocytomas formed within 3 weeks, which histopathologically and genetically resembled human glioblastoma and proved to be fatal with a median survival of 25 days. To further evaluate the relationship between adult neural stem/progenitor cells in the SVZ and astrocytoma initiating cells, we crossed TRP GEMM with knock-in Sox2-GFP reporter mice to purify TRP neural stem cells from the SVZ. These cells were then stereotactically injected into the diencephalon of syngeneic recipient mice. Allograft cells, identified by GFP expression, were found proliferating around the injection site several weeks after injection, suggestive of developing astrocytomas. Some cells also migrated along white matter tracks and infiltrated the stem cell niche in the subventricular zone. These results suggest that GFAP+ NSC within the SVZ, and potentially GFAP+ astrocytes elsewhere in the neuraxis, may serve as the cell-of-origin for diffuse astrocytomas in the adult murine brain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3302. doi:1538-7445.AM2012-3302