Neuroblastoma-A Neural Crest Derived Embryonal Malignancy

Abstract

Neuroblastoma is a neural crest derived malignancy of the peripheral nervous system and is the most common and deadliest tumor of infancy. It is characterized by clinical heterogeneity with a disease spectrum ranging from spontaneous regression without any medical intervention to treatment resistant tumors with metastatic spread and poor patient survival. The events that lead to the development of neuroblastoma from the neural crest have not been fully elucidated. Here we discuss factors and processes within the neural crest that when dysregulated have the potential to be initiators or drivers of neuroblastoma development. A more precise biological understanding of neuroblastoma causes and cell of origin is highly warranted. This will give valuable information for the development of medicines that specifically target molecules within neuroblastoma cells and also give hint about the mechanisms behind treatment resistance that is frequently seen in neuroblastoma.

Keywords: mutation; neural crest; neuroblastoma; oncogenic drivers; tumorigenesis.

Figure 1

Neuroblastoma development from neural crest. During embryogenesis cells within the neural crest undergo epithelial-to-mesenchymal transition (EMT) enabling cells to delaminate, migrate and differentiate into a wide range of cell types that contributes to anatomical structures within the organism. This process is regulated by a complex set of external signaling, activation of transcriptional programs and epigenetic events. Dysregulation of factors involved in this process can induce changes in cell specification and deregulated-migration and -cell differentiation giving rise to hyperneoplastic lesions that eventually can result in neuroblastoma. These events can occur during different stages of neural crest maturation and factors that are thought to be important for neuroblastoma development are boxed in red. Dysregulated expression of MYCN is the most powerful oncogenic driver for neuroblastoma and induces proliferation and inhibits apoptosis of sympathoadrenal lineage cells whereas LIN28B control MYCN expression via regulating Let-7 miRNA. Anaplastic lymphoma kinase (ALK) and paired-like homeobox 2B (PHOX2B) are germline mutations found in neuroblastoma. Rho signaling is crucial for the migration of neural crest cells by controlling contact inhibition of locomotion between neural crest cells. SWI/SNF complexes are tumor suppressors that for coordinate diverse chromatin alterations which influences the transcriptional output, DNA replication and repair.