title: Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas.
abstract: Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome.
authors.affiliation: Neuroscience Centre, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Sutter
authors.forename: O
authors.initials: O
authors.lastname: Shakhova
authors.forename: H
authors.initials: H
authors.lastname: Bhagat
authors.forename: H
authors.initials: H
authors.lastname: Behesti
authors.forename: C
authors.initials: C
authors.lastname: Sutter
authors.forename: S
authors.initials: S
authors.lastname: Penkar
authors.forename: A
authors.initials: A
authors.lastname: Santuccione
authors.forename: R
authors.initials: R
authors.lastname: Bernays
authors.forename: F L
authors.initials: FL
authors.lastname: Heppner
authors.forename: U
authors.initials: U
authors.lastname: Schüller
authors.forename: M
authors.initials: M
authors.lastname: Grotzer
authors.forename: H
authors.initials: H
authors.lastname: Moch
authors.forename: P
authors.initials: P
authors.lastname: Schraml
authors.forename: S
authors.initials: S
authors.lastname: Marino
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000145:classification / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D002531:Cerebellum / Q000473:pathology*; D004195:Disease Models, Animal; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D008527:Medulloblastoma / Q000145:classification / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009474:Neurons / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D013234:Stem Cells / Q000473:pathology*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D055758:SOX9 Transcription Factor; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C527933:Sox9 protein, mouse