Development of a novel mouse glioma model using lentiviral vectors

There is a need for mouse tumor models that more closely recapitulate the pathophysiology of human cancers. Here, a mouse model of glioblastoma multiforme (GBM) is generated with Cre-loxP controlled, lentiviral-mediated delivery of the oncogenes H-Ras and AKT. Transduction of the oncogenes in a small number of cells in adult immunocompetent mice led to the formation of GBM-like tumors, particularly when combined with loss of p53. We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP–controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein–positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme–like tumors, which contained CD133+ cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the use of Cre-loxP–controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.