Activation of oncogenic k‐ras in glioneuronal precursor cells results in simultaneous expansion of the subventricular zone and infiltrating glioma

Abstract

A subset of neoplastic cells within human high‐grade gliomas has been shown to possess stem cell‐like properties. These cells may sustain glioma growth, and their unique properties may confer resistance to current glioma treatments. Whether glioma stem cells derive from indigenous neural stem cells or from tumor cells that have re‐acquired stem cell‐like properties is unknown. To address this, we activated oncogenic K‐ras in mouse glioneuronal precursor cells using GFAP‐Cre. GFAP‐Cre/K‐rasG12D mice showed a marked expansion of the subventricular zone/rostral migratory stream (SVZ/RMS), a stem cell population in the mature rodent brain. Each mouse (n =7) also developed bilateral, intermediate grade, infiltrating glioma. Tumors were characterized by hyperchromatic, angular cells, satellitosis of neurons, scattered mitotic figures, elevated Ki67 labeling, and GFAP expression. Tumors were consistently located in the amygdalohippocampal region and nearby cortex, often in association with the lateral ventricle. In some cases, foci of infiltrating tumor were contiguous with the expanded SVZ/RMS. Tumor cells expressed markers associated with neural progenitor cells, including Olig2 and PDGFR‐α. These data strongly suggest that the infiltrating tumor cells are derived from neural stem cells transformed by activation of oncogenic K‐ras and provide an animal model for investigating the role of neural stem cells in gliomagenesis. This work was supported by a Vanderbilt Physician Scientist Development award (TWA).