Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
Cell Tissue Res. 2018 May;372(2):223-232. doi: 10.1007/s00441-017-2702-0. Epub 2017 Oct 13.
Neuroblastoma is a pediatric solid tumor arising from embryonic neural crest progenitor cells that normally generate the peripheral sympathetic nervous system. As such, the location of neuroblastoma tumors is correlated with the distribution of major post-ganglionic clusters throughout the sympathetic chain, with the highest incidence in the adrenal medulla or lumbar sympathetic ganglia (~65%). Neuroblastoma is an enigmatic tumor that can spontaneously regress with minimal treatment or become highly metastatic and develop resistance to aggressive treatments, including radiation and high-dose chemotherapy. Age of diagnosis, stage of disease and cellular and genetic features often predict whether the tumor will regress or advance to metastatic disease. Recent efforts using molecular and genomic technologies have allowed more accurate stratification of patients into low-, intermediate- and high-risk categories, thereby allowing for minimal intervention in low-risk patients and providing potential new therapeutic targets, such as the ALK receptor tyrosine kinase, for high-risk or relapsed patients. Despite these advances, the overall survival of high-risk neuroblastoma patients is still less than 50%. Furthermore, next-generation sequencing has revealed that almost two-thirds of neuroblastoma tumors do not contain obvious pathogenic mutations, suggesting that epigenetic mechanisms and/or a perturbed cellular microenvironment may heavily influence neuroblastoma development. Understanding the mechanisms that drive neuroblastoma, therefore, will likely require a combination of genomic, developmental and cancer biology approaches in whole animal systems. In this review, we discuss the contributions of zebrafish research to our understanding of neuroblastoma pathogenesis as well as the potential for this model system to accelerate the identification of more effective therapies for high-risk neuroblastoma patients in the future.
神经母细胞瘤是一种起源于胚胎神经嵴祖细胞的小儿实体肿瘤，这些细胞通常会生成外周交感神经系统。因此，神经母细胞瘤的位置与交感神经链中主要节后神经丛的分布相关，在肾上腺髓质或腰椎交感神经节处的发病率最高（约 65%）。神经母细胞瘤是一种神秘的肿瘤，在接受最少治疗时可能会自发消退，也可能会高度转移并对包括放疗和高剂量化疗在内的侵袭性治疗产生耐药性。诊断时的年龄、疾病分期以及细胞和遗传特征通常可以预测肿瘤是消退还是进展为转移性疾病。最近利用分子和基因组技术的努力使得对患者进行更准确的分层，分为低危、中危和高危人群，从而使低危患者的干预最小化，并为高危或复发患者提供了新的潜在治疗靶点，如 ALK 受体酪氨酸激酶。尽管取得了这些进展，但高危神经母细胞瘤患者的总体生存率仍低于 50%。此外，下一代测序显示，近三分之二的神经母细胞瘤肿瘤不含有明显的致病性突变，这表明表观遗传机制和/或细胞微环境的紊乱可能会严重影响神经母细胞瘤的发展。因此，了解驱动神经母细胞瘤的机制可能需要在全动物系统中结合基因组学、发育生物学和癌症生物学方法。在这篇综述中，我们讨论了斑马鱼研究对我们理解神经母细胞瘤发病机制的贡献，以及该模型系统在未来加速为高危神经母细胞瘤患者确定更有效治疗方法的潜力。
