The origins of medulloblastoma subtypes.
ABSTRACT Childhood tumors containing cells that are morphologically and functionally similar to normal progenitor cells provide fertile ground for investigating the links between development and cancer. In this respect, integrated studies of normal cerebellar development and the medulloblastoma, a malignant embryonal tumor of the cerebellum, have proven especially fruitful. Emerging evidence indicates that the different precursor cell populations that form the cerebellum and the cell signaling pathways that regulate its development likely represent distinct compartments from which the various subtypes of medulloblastoma arise. Definitive characterization of each medulloblastoma subtype will undoubtedly improve treatment of this disease and provide important insights to the origins of cancer.
SourceAvailable from: Giselle Suero[Show abstract] [Hide abstract]
ABSTRACT: Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15 minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm(3). Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual Ptch1-CKO mice. These results show that MEMRI provides a powerful method for early in vivo detection and longitudinal imaging of MB progression in the mouse brain.Neoplasia (New York, N.Y.) 12/2014; 16(12):993. DOI:10.1016/j.neo.2014.10.001 · 5.40 Impact Factor
Article: SnapShot: Medulloblastoma[Show abstract] [Hide abstract]
ABSTRACT: Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the classification of MB subgroups, historically by histopathology and currently based on genomic information. Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy. Copyright © 2014 Elsevier Inc. All rights reserved.Cancer Cell 12/2014; 26(6):940-940.e1. DOI:10.1016/j.ccell.2014.11.015 · 23.89 Impact Factor
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ABSTRACT: Disrupted differentiation during development can lead to oncogenesis, but the underlying mechanisms remain poorly understood. Here we identify BCL6, a transcriptional repressor and lymphoma oncoprotein, as a pivotal factor required for neurogenesis and tumor suppression of medulloblastoma (MB). BCL6 is necessary for and capable of preventing the development of GNP-derived MB in mice, and can block the growth of human MB cells in vitro. BCL6 neurogenic and oncosuppressor effects rely on direct transcriptional repression of Gli1 and Gli2 effectors of the SHH pathway, through recruitment of BCOR corepressor and SIRT1 deacetylase. Our findings identify the BCL6/BCOR/SIRT1 complex as a potent repressor of the SHH pathway in normal and oncogenic neural development, with direct diagnostic and/or therapeutic relevance for SHH MB.Cancer Cell 12/2014; 26(6):797. DOI:10.1016/j.ccell.2014.10.021 · 23.89 Impact Factor