Medulloblastomas and other embryonal neoplasms are the most common malignant brain tumors in children. It has become clear that signaling pathways controlling normal central nervous system development are often dysregulated in medulloblastomas. Mutations activating Wnt and Hedgehog signaling are found in many of these tumors. Interestingly, both of these pathways promote survival and proliferation of central nervous system progenitor cells. Fan et al. and Hallahan et al. now show that the Notch signal transduction pathway, which also regulates brain progenitor cell survival, is activated in medulloblastomas as well. Hallahan et al. created a new transgenic model of medulloblastoma (ND2:SmoA1) with elevated Hedgehog activity that develops tumors in 48% of mice at a mean age of 25.7 weeks (upper left). Transcriptional analysis of these mice revealed Notch signaling in tumors but not non-neoplastic cerebellum. Additional analyses showed that subsets of human medulloblastomas overexpressed Notch1 and/or Notch2 as well (Notch1 immunohistochemistry in human medulloblastoma, upper right). Fan et al. also found overexpression of Notch pathway components in human tumors, and documented amplification of the Notch2 locus in a small subset of cases (fluorescence in situ hybridization for Notch2 in red and a distal control locus in green, lower left). Hes1, a Notch target, was analyzed immunohistochemically and was associated with poor outcome in children with medulloblastoma (lower right). Both groups show that blockade of Notch signaling using gamma-secretase inhibitors slowed growth of medulloblastoma cell lines, suggesting Notch represents a new therapeutic target in these aggressive tumors. For details, see the articles in this issue by Fan et al. and Hallahan et al. on pages 7787 and 7794, respectively.

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