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Origin and initiation mechanisms of neuroblastoma

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Abstract

Neuroblastoma is an embryonal malignancy that affects normal development of the adrenal medulla and paravertebral sympathetic ganglia in early childhood. Extensive studies have revealed the molecular characteristics of human neuroblastomas, including abnormalities at genome, epigenome and transcriptome levels. However, neuroblastoma initiation mechanisms and even its origin are long-standing mysteries. In this review article, we summarize the current knowledge about normal development of putative neuroblastoma sources, namely sympathoadrenal lineage of neural crest cells and Schwann cell precursors that were recently identified as the source of adrenal chromaffin cells. A plausible origin of enigmatic stage 4S neuroblastoma is also discussed. With regard to the initiation mechanisms, we review genetic abnormalities in neuroblastomas and their possible association to initiation mechanisms. We also summarize evidences of neuroblastoma initiation observed in genetically engineered animal models, in which epigenetic alterations were involved, including transcriptomic upregulation by N-Myc and downregulation by polycomb repressive complex 2. Finally, several in vitro experimental methods are proposed that hopefully will accelerate our comprehension of neuroblastoma initiation. Thus, this review summarizes the state-of-the-art knowledge about the mechanisms of neuroblastoma initiation, which is critical for developing new strategies to cure children with neuroblastoma.

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Funding

S. Tsubota was supported by a Grant-in-Aid for JSPS Research Fellow (14 J00157). K. Kadomatsu was supported by grants for the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (16ck0106011h0003), JSPS KAKENHI Grant Number JP15k15079, and CREST, JST (15656320).

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  1. Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan

    Shoma Tsubota & Kenji Kadomatsu

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  1. Shoma Tsubota
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Correspondence to Kenji Kadomatsu.

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Tsubota, S., Kadomatsu, K. Origin and initiation mechanisms of neuroblastoma. Cell Tissue Res 372, 211–221 (2018). https://doi.org/10.1007/s00441-018-2796-z

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