Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting

Abstract

Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.

Keywords: Neural crest; Neuroblastoma; Cancer stem cells; Polyploid giant cancer cells molecular mechanisms; Therapeutic targeting; Tumour microenvironment

Core Tip: Cancer stem cells promote tumour-heterogeneity, post-therapeutic relapse and metastatic progression in neuroblastomas (NBs), by way of their drug-resistant, self-renewing and reversibly plastic phenotypes, and are, therefore, critical targets to eliminate if improvements in therapeutic outcomes are to be realized. Despite progress in understanding the molecular mechanisms that underpin NB cancer stem cell (CSC) selection, promotion and maintenance, efficacious CSC targeting remains difficult. Here we review the molecular mechanisms considered to regulate NB CSCs, together with the therapeutic strategies and future prospects for their eradication, highlighting the need for a better understanding and targeting of polyploid giant cancer cell states, future prospects for chimeric antigen receptor (CAR) cell immunotherapies, the need to identify additional functional cell surface NB CSC-specific targets and to develop better models for NB CSC experimental therapeutics.