MYCN Function in Neuroblastoma Development

Abstract

Dysregulated expression of the transcription factor MYCN is frequently detected in nervous system tumors such as childhood neuroblastoma. Here, gene amplification of MYCN is a single oncogenic driver inducing neoplastic transformation in neural crest-derived cells. This abnormal MYCN expression is one of the strongest predictors of poor prognosis. It is present at diagnosis and is never acquired during later tumorigenesis of MYCN non-amplified neuroblastoma. This suggests that increased MYCN expression is an early event in these cancers leading to a peculiar dysregulation of cells that results in embryonal or cancer stem-like qualities, such as increased self-renewal, apoptotic resistance, and metabolic flexibility.

Keywords: MYCN; cancer stem cell; childhood cancer; neural crest; neuroblastoma.

Figure 1

N-MYC acts as a Cancer Stem Cell Factor in the Developing Neural Crest and Promotes Tumorigenesis in Neuroblastoma. Upper Panel: The neural crest is a transient structure located in the neural plate border, an area between the neural plate and the non-neural ectoderm. From the neural crest, multipotent progenitor cells delaminate, migrate through epithelial-to-mesenchymal-transition (EMT), and differentiate into versatile structures within the whole organism. Lower Panel: While C-Myc is the main regulator in pluripotent cells of early embryonal development, MycN is highly expressed in the multipotent cells of the migratory and post-migratory neural crest. During differentiation, MycN expression is downregulated and the sympathoadrenal precursor cells or progenitor cells mature into different cell types of the autonomic neural cell lineage (see asterisk), such as sympathetic ganglion cells, chromaffin cells of the adrenal medulla or cells of the peripheral nervous system. Even though there is strong evidence that MYCN gene amplification is an early and maybe initiating event, it has not been proven yet when and how the amplification takes place. The aberrant expression of MYCN induces a unique cancer stem cell-like phenotype by enabling infinite self-renewal, apoptotic resistance, and via metabolic reprogramming characterized by increased glycolysis together with an active oxidative phosphorylation. The establishing neuroblastoma consists of heterogeneous cell populations.