title: Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma.
abstract: Activating mutations in the gene encoding β-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a histologically benign but aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours. Recently, we generated an ACP mouse model and revealed that, as in human ACP, nucleocytoplasmic accumulation of β-catenin (β-cat(nc)) and over-activation of the Wnt/β-catenin pathway occurs only in a very small proportion of cells, which form clusters. Here, combining mouse genetics, fluorescence labelling and flow-sorting techniques, we have isolated these cells from tumorigenic mouse pituitaries and shown that the β-cat(nc) cells are enriched for colony-forming cells when cultured in stem cell-promoting media, and have longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells (PSCs). Global gene profiling analysis has revealed that these β-cat(nc) cells express high levels of secreted mitogenic signals, such as members of the SHH, BMP and FGF family, in addition to several chemokines and their receptors, suggesting an important autocrine/paracrine role of these cells in the pathogenesis of ACP and a reciprocal communication with their environment. Finally, we highlight the clinical relevance of these findings by showing that these pathways are also up-regulated in the β-cat(nc) cell clusters identified in human ACP. As well as providing further support to the concept that pituitary stem cells may play an important role in the oncogenesis of human ACP, our data reveal novel disease biomarkers and potential pharmacological targets for the treatment of these devastating childhood tumours.
authors.affiliation: Neural Development Unit, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Andoniadou
authors.forename: Carles
authors.initials: C
authors.lastname: Gaston-Massuet
authors.forename: Rukmini
authors.initials: R
authors.lastname: Reddy
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Schneider
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.forename: Paul
authors.initials: P
authors.lastname: Le Tissier
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.forename: Larysa H
authors.initials: LH
authors.lastname: Pevny
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003397:Craniopharyngioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009154:Mutation; D014411:Neoplastic Stem Cells; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051176:beta Catenin