Novel aspects of neuroblastoma : to hypoxia and beyond

Neuroblastoma (NB) is a pediatric cancer arising from the neural crest cells forming the sympathetic nervous system. Just as other types of pediatric cancer the driving mutations of neuroblastoma are few and the tumors are instead categorized according to genetic abbreviations such as amplification, loss of heterozygosity, gains and translocations. Neuroblastoma continues to be therapeutically challenging and flabbergasts scientists and doctors with it vast heterogeneity both clinically and biologically. The tumors range from aggressive, fast growing, lethal cancer to metastatic tumors that will spontaneously regress and disappear without any clinical interventions. The survivors of high-risk neuroblastoma struggle with life-long side effects due to the aggressive therapeutic treatment used in these young children. In this thesis I have focused on discovering alternative mechanisms that can contribute to the development and malignancy of neuroblastoma. Paper I. High-risk neuroblastoma has been shown to have high level of DNA methylation of putative tumor suppressors. We designed a therapeutic strategy where we exploited the reversibility of DNA methylation and combined the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) with the differentiation-promoting activity of retinoic acid (RA) as an alternative strategy to treat high-risk neuroblastoma. In this paper we showed that treatment with AZA restores high-risk neuroblastomas sensitivity to RA. Additionally, the combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival in vivo. Genomewide analysis of treated tumors revealed that the combined treatment induced a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. We performed a loss-of-function experiment using a small-molecule inhibitor of HIF2α which resulted in diminished tumor response to AZA+RA treatment. Our study indicated that the increase in HIF2α levels is a key component in ...