Biological and clinical relevance of neural stem cells in the pathogenesis of childhood medulloblastoma

Paediatric brain tumours have overtaken leukaemias as the leading cause of cancer-related death in children despite being only half as common. Medulloblastoma (MB), the most common type of malignant paediatric brain tumour, is a heterogeneous group with at least five histological and four molecular subtypes. Despite major progress in the understanding of the genetic and molecular pathogenesis of MB, relapse rate and side effects remain major concerns. The existence of multiple MB subtypes suggests that the current clinical categorisation of two risk stratification groups is inadequate and highlights the need for more tailored therapeutic strategies. The best understood subtype comprises sonic hedgehog (SHH)-dependent MB. Several components of the SHH pathway are viable drug targets that may translate to effective subtype-specific treatment options in the near future. Similarly, subtype-specific targets for clinical intervention are being investigated in other molecular variants of MB. Some MB may rely on a small population of CD133+ tumour cells termed brain tumour stem cells (BTSCs) that phenotypically and functionally resemble normal CD133+ neural stem cells (NSCs) in the developing foetal brain. The resemblance suggests that BTSCs could arise from transformed NSCs residing in the cerebellum. BTSCs are more resistant to therapy and are not effectively targeted by current treatments. New methodologies allow the generation, maintenance and manipulation of human NSCs and BTSCs, providing valuable tools and reagents for studying the mechanisms of neoplastic deregulation. The development of NSC- and BTSC-based models may be of benefit for elucidating the underlying molecular mechanisms of MB pathogenesis and facilitate transition of new knowledge into clinical setting in the future.