Neuroblastoma pathogenesis: deregulation of embryonic neural crest development

Abstract

Neuroblastoma (NB) is an aggressive pediatric cancer that originates from neural crest tissues of the sympathetic nervous system. NB is highly heterogeneous both from a clinical and a molecular perspective. Clinically, this cancer represents a wide range of phenotypes ranging from spontaneous regression of 4S disease to unremitting treatment-refractory progression and death of high-risk metastatic disease. At a cellular level, the heterogeneous behavior of NB likely arises from an arrest and deregulation of normal neural crest development. In the present review, we summarize our current knowledge of neural crest development as it relates to pathways promoting 'stemness' and how deregulation may contribute to the development of tumor-initiating CSCs. There is an emerging consensus that such tumor subpopulations contribute to the evolution of drug resistance, metastasis and relapse in other equally aggressive malignancies. As relapsed, refractory disease remains the primary cause of death for neuroblastoma, the identification and targeting of CSCs or other primary drivers of tumor progression remains a critical, clinically significant goal for neuroblastoma. We will critically review recent and past evidence in the literature supporting the concept of CSCs as drivers of neuroblastoma pathogenesis.

Keywords: Cancer stem cells; G-CSF receptor (CD114); Neural crest; Neuroblastoma.

Figure 1. Neural crest development and neuroblastoma pathogenesis

NC development is a tightly regulated process beginning with neural tube formation and ending with the formation of terminally differentiated NC derivatives, including the sympathoadrenal lineages. Each step of the process is controlled by cascades of signaling pathways and activation of key transcription factors. The exact stage along this pathway where NB originates still remains unknown; however, key pathways highlighted below have been shown to contribute to ‘stemness’ and may be involved in the formation of tumor initiating NB CSCs.