Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas.

Sandra Cantilena 1,4 , Fabio Pastorino 3,4 , Annalisa Pezzolo 3 , Olesya Chayka 1 , Vito Pistoia 3 , Mirco Ponzoni 3 and Arturo Sala 1,2 1 Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, 30 Guilford st London WC1N 1EH London UK 2 Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge, Middlesex UB8 3PH, UK 3 Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16147 Genova, Italy 4 Denotes equal contribution Received: December 30, 2011; Accepted: December 30, 2011; Published: December 31, 2011; Keywords: HIF, hypoxia, metastasis, neuroblastoma, stem cell Correspondence: Arturo Sala, email: // Mirco Ponzoni, email: // // 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.