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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Doxorubicin / pharmacology
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Frizzled Receptors / genetics
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Frizzled Receptors / metabolism*
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Humans
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Hypoxia
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Mice
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Neuroblastoma / genetics
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Neuroblastoma / metabolism*
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Neuroblastoma / pathology
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Nuclear Proteins / metabolism
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Prognosis
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RNA Interference
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RNA, Small Interfering
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Receptor, Notch1 / metabolism
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Tumor Cells, Cultured
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Twist-Related Protein 1 / metabolism
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Wnt Signaling Pathway / genetics
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor
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FZD6 protein, human
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Frizzled Receptors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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NOTCH1 protein, human
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Nuclear Proteins
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RNA, Small Interfering
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Receptor, Notch1
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TWIST1 protein, human
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Twist-Related Protein 1
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endothelial PAS domain-containing protein 1
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Doxorubicin