Article

Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Development (Impact Factor: 6.27). 06/2005; 132(10):2425-39. DOI: 10.1242/dev.01793
Source: PubMed

ABSTRACT 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.
    Developmental Cell 09/2014; 31(1). DOI:10.1016/j.devcel.2014.08.010 · 10.37 Impact Factor
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    • "In single mutant mouse (Ptch1þ/À) brain, though heterozygosity of Ptch1 locus is sufficient to initiate the disease, preneoplastic cells, having characteristics of GNPs and destined to the fate of MB cells, show gradual decay in expression of the remaining wild-type Ptch1 allele. The disappearance of Ptch1 expression as quantified by real-time PCR analysis suggests that loss of the remaining wild-type Ptch1 is essential for the growth of tumor in heterozygous condition (Berman et al., 2002; Oliver et al., 2005). Previously, a few studies reported a continued basal level expression of wild-type Ptch1 by RT-PCR, Northern blot analysis of total RNA, sequencing and in situ hybridization of cDNA isolated from these primary tumors (Romer et al., 2004; Wetmore et al., 2000; Zurawel et al., 2000). "
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    ABSTRACT: Since its identification Patched1 (Ptch1) has gained importance for playing a cardinal role in developmental patterning through Hedgehog (Hh) pathway, acting as a transmembrane receptor. Involvement of this protein in diverse aspects of the neuronal system, from development to regeneration and protection, including uncontrolled proliferation in oncogenic perspectives, makes it an intriguing candidate for investigation in neurobiology. Stem cell population of adult nervous system is also found to be regulated by Ptch1. Though not elaborately studied, research in this field for the past one decade has suggested a new spectrum of Ptch1 function through an alternative route independent of Hh. In this chapter, the available knowledge about Ptch1 in neuronal system is critically reviewed and further functional insights about this protein are evaluated.
    Vitamins & Hormones 01/2012; 88:439-59. DOI:10.1016/B978-0-12-394622-5.00019-5 · 1.78 Impact Factor
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    • "In our experiments, tumor cells had complete loss of Ptch1 expression as a collaborating oncogenic event. It is not clear in other Ptch1 þ /À medulloblastoma models whether Ptch1 was expressed or silenced (Wetmore et al., 2000; Romer et al., 2004; Oliver et al., 2005), with the use of specific Ptch1 primers critical in the determination of Ptch1 expression (Oliver et al., 2005). Our studies are consistent with the complete loss of Ptch1 expression being a necessary event for tumor progression. "
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    ABSTRACT: Medulloblastoma tumorigenesis caused by inactivating mutations in the PATCHED1 (PTCH1) gene is initiated by persistently activated Sonic Hedgehog (Shh) signaling in granule neuron precursors (GNPs) during the late stages of cerebellar development. Both normal cerebellar development and Shh-driven medulloblastoma tumorigenesis require N-Myc expression. However, the mechanisms by which N-Myc affects the stages of medulloblastoma initiation and progression are unknown. Here we used a mouse model of Ptch1 heterozygosity and medulloblastoma to show that increased N-Myc expression characterized the earliest selection of focal GNP hyperplasia destined for later tumor progression. Step-wise loss of Ptch1 expression, from tumor initiation to progression, led to incremental increases in N-Myc protein, rather than mRNA, expression. Increased N-Myc resulted in enhanced proliferation and death resistance of perinatal GNPs at tumor initiation. Sequential N-Myc protein phosphorylation at serine-62 and serine-62/threonine-58 characterized the early and late stages of medulloblastoma tumorigenesis, respectively. Shh pathway activation led to increased Myc protein stability and reduced expression of key regulatory factors. Taken together our data identify N-Myc protein stability as the result of loss of Ptch1, which distinguishes normal cerebellar development from medulloblastoma tumorigenesis.
    Oncogene 03/2009; 28(13):1605-15. DOI:10.1038/onc.2009.3 · 8.56 Impact Factor
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