Zebrafish as a model to study neuroblastoma development

Abstract

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.

Pediatric Cancer Models in Zebrafish

“…Zebrafish cancer models have accelerated the discovery of new mechanisms driving human cancers and identified new drugs for clinical trials [6]. A number of recent reviews detailing the experimental approaches for generating different leukemia [7], sarcoma [8], neuroblastoma [9], and germ-cell tumor [10] models are published elsewhere. Here, we focus on how genetically engineered zebrafish lines that specifically model pediatric and adolescent cancers, which we [11,36]) with corresponding anatomical tumor location in zebrafish are illustrated.…”

“…Zebrafish Models of Neuroblastoma Amplification of MYCN is observed in~20% of NBs and is associated with a poor prognosis [46]. Zebrafish models of NB are driven by targeted expression of the human MYCN gene to the developing peripheral sympathetic nervous system using the dopamine-β-hydroxylase (dβh) promoter [9]. Zebrafish models of NB with both low (17%) and high (70%) penetrance have been developed in order to detect cooperating mutations that either increase or decrease tumor burden, respectively [48,49].…”

Tipping the Scales With Zebrafish to Understand Adaptive Tumor Immunity

“…Through exhaustive comparison of the human and zebrafish genome assemblies, it was found that 82% of disease-causing human genes have at least one zebrafish ortholog ( Howe et al, 2013 ). This level of conservation has led to the development of a wide array of cancer models in zebrafish ( Casey and Stewart, 2018 ; Hason and Bartůněk, 2019 ; Casey and Stewart, 2020 ; Elliot, 2020 ). Through the years of ongoing research, the pathological similarities of cancer and preservation of the immune components have also been well established between zebrafish and humans.…”

Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation

“…In addition, activation of the tyrosine kinase neurotrophin receptors TrkA and TrkB leads to apoptotic/differentiation neuroblast responses or to survival/proliferative effects, respectively [35,36,37]. Several animal models suitable to the study of NB differentiation and transformation have been generated, mainly centered in MYCN amplification and ALK hyperactivation [38,39]. NB cell differentiation can also be triggered in vitro by culturing NB cells in the presence of differentiation factors, such as retinoids (retinoic acid, RA), phorbol esters (phorbol 12-myristate 13-acetate, PMA), and neurotrophins (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF) [40,41].…”