In search of the medulloblast: Neural stem cells and embryonal brain tumors

Medulloblastomas have a cellular and molecular phenotype similar in many ways to that of neural stem cells. Indeed, it has long been believed that a medulloblastoma can arise from transformed neural stem cells. Recent analyses of murine transgenic lines has confirmed that cells of the external germinal layer (EGL) can be transformed into a medulloblastoma, generally in association with activation of the Hedgehog signaling pathway. Stem or progenitor cell populations outside the EGL, however, are also likely the cells of origin for a subset of medulloblastomas. Many nonnodular tumors, for example, express markers suggesting that they derive from the ventricular zone germinal layer and show evidence of Wnt pathway activation. Understanding the role of developmental signaling pathways, such as Hedgehog and Wnt, in the initiation and growth of embryonal brain tumors may lead to novel therapies for these highly malignant lesions. In addition, because such pathways are required in neural stem cells, their blockade may prove particularly effective in ablating the stem-like cells within medulloblastomas that are critical for tumor propagation. In support of this concept, inhibition of a third pathway important in stem cells, Notch, seems to deplete the stem-like tumor fraction and block formation of xenografts.