title: Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas.
abstract: Wnt signalling is an important component of vertebrate development, required for specification of the neural crest. Ten Wnt receptors [Frizzled receptor 1-10 (Fzd1-10)] have been identified so far, some of which are expressed in the developing nervous system and the neural crest. Here we show that expression of one such receptors, Fzd6, predicts poor survival in neuroblastoma patients and marks rare, HIF1/2 α-positive cells in tumour hypoxic areas. Fzd6 positive neuroblastoma cells form neurospheres with high efficiency, are resistant to doxorubicin killing and express high levels of mesenchymal markers such as Twist1 and Notch1. Expression of Fzd6 is required for the expression of genes of the non-canonical Wnt pathway and the spheres forming activity. When transplanted into immunodeficient mice, neuroblastoma cells expressing the Fzd6 marker grow more aggressively than their Fzd6 negative counterparts. We conclude that Fzd6 is a new surface marker of aggressive neuroblastoma cells with stem cell-like features.
authors.affiliation: Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, 30 Guilford st London WC1N 1EH London UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cantilena
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pezzolo
authors.forename: Olesya
authors.initials: O
authors.lastname: Chayka
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Arturo
authors.initials: A
authors.lastname: Sala
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D051157:Frizzled Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051879:Twist-Related Protein 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C484687:FZD6 protein, human; C497442:HIF1A protein, human; C497761:NOTCH1 protein, human; C103173:TWIST1 protein, human