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.
Highlights
Neuroblastoma, the most common extracranial solid tumor in infancy, is an embryonic cancer originating from the neural crest [1]
We initially investigated whether frizzled receptors were associated with survival of neuroblastoma patients
Using the neuroblastoma prognosis databases on the Oncogenomics repository, we found that only Fzd6, among the 10 frizzled receptors, was statistically significantly associated with poor survival in all databases
Summary
Neuroblastoma, the most common extracranial solid tumor in infancy, is an embryonic cancer originating from the neural crest [1]. To investigate whether the expression of Fzd6 could be compatible with a stem cell-like phenotype, we FACS-sorted Fzd6 positive and negative cells from the neuroblastoma cell line R6-2, recently established by our group from MYCN mice [14], since these cells were enriched in Fzd6 positive cells compared to others (Fig. 2). We observed that Fzd6-positive neuroblastoma cells formed more neurospheres in serum free medium and were more invasive than their Fzd6-negative counterparts in in vitro invasion assays (Fig. 3 A,B).
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