Neural Stem Cells in Brain Tumor Development

摘要: Malignant astrocytomas are highly invasive and incurable brain tumors. Mouse models that genetically resemble the human disease are valuable tools in understanding the pathogenesis of these malignancies. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors Nf1, p53 and Pten. Through somatic loss of heterozygosity, these mice develop varying grades of astrocytic malignancy with 100% penetrance. Studies on our tumor suppressor mouse models indicated a central role for neural stem cells and stem cell-like cancer cells in malignant astrocytoma formation. Using stereotactic viral cre-mediated approach, we demonstrate that targeting of tumor suppressor inactivating mutations in the subventricular zone (SVZ) where neural stem and progenitor cells reside is both necessary and sufficient to induce astrocytoma formation. We also show evidence of spontaneous differentiation and infiltration of these cancer-initiating cells in situ during tumor development. These studies have so far shown that neural stem cells or its progeny can give rise to astrocytomas. Neural stem cells, which have unlimited self-renewal potential, produce transit amplifying cells, or progenitor cells, which undergo limited mitoses before differentiating into more mature cell types. By genetically targeting transit amplifying cells using the Ascl1-creERT2 transgenic mouse, we show that tumor suppressor inactivation in the progenitor compartment alone induces malignant astrocytoma formation. Defects in proliferation, differentiation, and migration are likewise found several months prior to advanced …