Oliver TG, Read TA, Kessler JD, Mehmeti A, Wells JF, Huynh TT et al.. Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 132: 2425-2439

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Development (Impact Factor: 6.46). 06/2005; 132(10):2425-39. DOI: 10.1242/dev.01793
Source: PubMed


Medulloblastoma is the most common malignant brain tumor in children. It is thought to result from the transformation of granule cell precursors (GCPs) in the developing cerebellum, but little is known about the early stages of the disease. Here, we identify a pre-neoplastic stage of medulloblastoma in patched heterozygous mice, a model of the human disease. We show that pre-neoplastic cells are present in the majority of patched mutants, although only 16% of these mice develop tumors. Pre-neoplastic cells, like tumor cells, exhibit activation of the Sonic hedgehog pathway and constitutive proliferation. Importantly, they also lack expression of the wild-type patched allele, suggesting that loss of patched is an early event in tumorigenesis. Although pre-neoplastic cells resemble GCPs and tumor cells in many respects, they have a distinct molecular signature. Genes that mark the pre-neoplastic stage include regulators of migration, apoptosis and differentiation, processes crucial for normal development but previously unrecognized for their role in medulloblastoma. The identification and molecular characterization of pre-neoplastic cells provides insight into the early steps in medulloblastoma formation, and may yield important markers for early detection and therapy of this disease.

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    • "These groups of cells are called preneoplasia. The progression of these preneoplasia into advanced MBs requires additional genetic events; the most characterized being the loss of the second allele of Ptch1, or Ptch1 loss of heterozygosity (LOH) (Berman et al., 2002; Oliver et al., 2005; Pazzaglia et al., 2006; Uziel et al., 2005). Thus, preneoplasia are lesions where Ptch1 LOH has not occurred yet. "
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    ABSTRACT: During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.
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    • "In wild-type mice, by 3 weeks after birth, all GNPs have exited the cell cycle and migrated from the surface of the cerebellum into the IGL. In contrast, in Ptch1+/− mice, several GNPs continue to divide and remain on the surface of the molecular layer (ML), to form clusters of densely packed cells called pre-neoplastic lesions (PNLs) (Goodrich et al., 1997; Kim et al., 2003; Oliver et al., 2005). In 6 weeks old mice, the majority of PNLs have regressed, while only few progress to MBs. "
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