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.

Development and validation of a novel stemness-related prognostic model for neuroblastoma using integrated machine learning and bioinformatics analyses

“…Despite advances in the selection of CSCs in NB, targeting these cells effectively remains challenging ( 53 ). Our study examined the activity of signaling pathways associated with mRNAsi-related genes, and identified several drugs targeted at certain pathways that suggested better efficacy in the high-risk score group.…”

Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer

“…One possible explanation for this effect could be that the low growth rate lends more time for these cells to repair chemotherapy damage [106,107]. However, another phenomenon could contribute to this stage, such as higher expression of ABC drug transporters in these cells [108,109]. On the other hand, the effect that we attribute to the increase in slowly dividing cells could be due to other effects, such as the inhibition of angiogenesis, widely attributed and recently countersigned for the PEDF protein [110].…”

Long Non-Coding RNAs in Neuroblastoma: Pathogenesis, Biomarkers and Therapeutic Targets

“…For example, neuroblastoma-derived mesenchymal stem cells have been found to play a pro-tumoral role in the TME, promoting immune evasion and the invasion and metastasis of tumor cells [ 96 ]. The number of molecular elements identified as being linked mechanistically to stemness is also increasing [ 96 , 97 , 98 ]. Several signaling pathways, such as the PI3K/Akt/mammalian target of rapamycin (mTOR; PAM), Wnt, and RAS/RAF/MEK/ERK pathways, as well as dysregulated p53 signaling, are known to promote and maintain stemness in neuroblastoma.…”

“…VEGF has been identified as a factor that stimulates the survival, angiogenesis, and etoposide chemoresistance of neuroblastoma cells; recent studies conducted with murine xenograft models, however, have indicated that VEGF expression is not correlated with angiogenesis, but rather with the neural differentiation of neuroblastoma cells [ 119 , 120 , 121 , 122 ]. MALAT1 also contributes to the maintenance of stemness, promoting immune evasion, migration, invasion, and metastasis [ 98 ]. These effects are mediated via the PAM pathway, the RAS/RAF/MEK/ERK pathway, and the tyrosine kinase receptor Axl.…”

“…In recent years, the number of lncRNAs identified to play key roles in the regulation of chemosensitivity has increased greatly. It is becoming increasingly clear that other molecular factors and signaling pathways are also involved in this process, as discussed above [ 96 , 97 , 98 ]. Many lncRNAs mediate their effects through these signaling pathways, indirectly influencing chemosensitivity.…”