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. 2019 Dec 19;2(4):948-967.
doi: 10.20517/cdr.2019.72. Epub 2019 Nov 11.

Cancer stem cells in neuroblastoma therapy resistance

Natarajan Aravindan  1   2   3 , Drishti Jain  1 , Dinesh Babu Somasundaram  1 , Terence S Herman  1   4 , Sheeja Aravindan  4
Affiliations

Cancer stem cells in neuroblastoma therapy resistance

Natarajan Aravindan et al. Cancer Drug Resist. .

Abstract

Neuroblastoma (NB) is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths. This mortality rate has been attributed to the > 50% frequency of relapse despite intensive, multimodal clinical therapy in patients with progressive NB. Given the disease's heterogeneity and developed resistance, attaining a cure after relapse of progressive NB is highly challenging. A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells (CSCs). In this review, we present the current understanding of NB-CSCs, their intrinsic role in tumorigenesis, their function in disease progression, and their influence on acquired therapy resistance and tumor evolution. In particular, this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB, the function of pre-existing CSCs in NB progression and therapy response, the formation and influence of induced CSCs (iCSCs) in drug resistance and tumor evolution, and the development of a CSC-targeted therapeutic approach.

Keywords: Neuroblastoma; cancer stem cells; clonal selection; drug resistance; induced cancer stem cell; therapy resistance.

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Conflict of interest statement

DECLARATIONS Conflicts of interest All authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of cellular and molecular events in embryogenesis and diverted signaling events leading to NB genesis. SAPs undergo a Snail/Slug-dependent EMT that augments NCCs’ migratory abilities, allowing them to migrate out of the neural tube. The prompted migration, accompanied by regulation of DNA repair genes in SAPs, makes them vulnerable to many genomic alterations leading to the genesis of NB. While embryogenesis is a sequential step-down process from pluripotency to differentiation, advancing disease stages of NB progress successively from differentiated to undifferentiated self-renewing multipotent CSCs. NB: neuroblastoma; SAPs: sympathoadrenal progenitors; EMT: epithelial-mesenchymal transition; CSCs: cancer stem cells
Figure 2
Figure 2
A: Cartoon showing the models of NB-CSCs-associated tumor resistance and tumor relapse. Pre-existing NB-CSCs survive IMCT and undergo self-renewal, clonal expansion and development of non-stem tumor cells, resulting in tumor relapse. In parallel, the non-stem tumor cells that survive IMCT under unique circumstances undergo extensive genetic and molecular rearrangements that lead to their transformation into induced CSCs (iCSCs). Generation of iCSCs with unique stem-cell characteristics of self-renewal and expansion results in tumor maintenance and relapse. B: Schematic representation of the molecular characteristics of NB-CSCs (pre-existing NB-CSCs and induced iCSCs) and their signaling flow-through that dictates therapy resistance and NB disease evolution. IMCT: intensive multi-modal clinical therapy; NB: neuroblastoma; CSCs: cancer stem cells; iCSCs: induced cancer stem cells; N-Type: neuroblastic type cells; I-Type: intermediate type neuroblastoma cells; S-Type: Schwann-type cells
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