Medulloblastoma stem cells

Abstract

Medulloblastoma and other embronal brain tumors are similar in appearance and differentiation potential to neural stem and progenitor cells. Expression studies performed using human tumor samples, as well as the analysis of murine transgenic models, suggest that both multipotent cerebellar stem cells and lineage-restricted progenitors of the external germinal layer can be transformed into medulloblastoma by genetic alterations. These molecular changes frequently involve constitutive activation of signaling pathways such as Wnt, Hedgehog, and Notch, which play a key role in non-neoplastic neural stem cells. Pharmacologic blockade of the Hedgehog and Notch pathways suppresses the growth of medulloblastoma in culture and in vivo and may prove effective in targeting the small cancer stem-cell subpopulation required for tumor initiation and long-term propagation.

Fig. 1

Only true stem cells can self-renew indefinitely, and they give rise to a transiently proliferating group of progenitors that eventually differentiate. Evidence exists for transformation of both neural stem and progenitor cells into medulloblastoma, and it is possible that genetic changes could generate these tumors from a fully differentiated cell as well. It is not clear whether cancer stem cells in medulloblastoma derived from these various origins would have unique properties.

Fig. 2

Mutations activating Wnt have been identified primarily in the classic medulloblastoma subtype, which is thought to derive primarily from stem and/or progenitor cells of the ventricular zone. The external germinal layer (EGL), in contrast, is thought to give rise to nodular/desmoplastic medulloblastoma commonly associated with Hedgehog (Hh) pathway activation. Other cerebellar stem and progenitor cells have been described and may also give rise to medulloblastoma (modified from Louis et al). MB, medulloblastoma; PNET, primitive neuroectodermal tumor.

Fig. 3

Notch pathway blockade seems to preferentially deplete stem-like medulloblastoma cells, leaving behind better-differentiated cells no longer able to form tumor masses. Both differentiation and cell death are involved in loss of the putative cancer stem cell (CSC) subpopulation.