Cancer Stem Cells in Neuroblastoma: Expanding the Therapeutic Frontier.

Wassim Abou-Kheir,Hisham F Bahmad,Sahar Assi,Farah Chamaa,Tamara Abou-Antoun,Reda M Chalhoub

doi:10.3389/fnmol.2019.00131

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents.

Highlights

Stem cells are a class of multipotent undifferentiated cells, able to give rise to all cells in a particular tissue, organ or organism
We have previously reported on the reversible adaptive plasticity (RAP) in NB that may be rendering it highly malignant and chemotherapy-resistant, a mechanism by which NB cancer stem cell (CSC) maintain a dynamic ability to revert back-andforth between anchorage-independent treatment-evasive tumorspheres and anchorage-dependent, adherent cancer cells in response to environmental stressors, such as therapeutic agents, hypoxia, low pH levels and deprivation of growth factors (Chakrabarti et al, 2012)
The authors of this study demonstrated an important cross-talk between BORIS/CTCFL and Wnt/β-catenin signaling pathways that led to enhanced expression of stemness proteins and increased epithelial-to-mesenchymal transition (EMT) markers such as N-CAD, Vimentin and SNAIL

Summary

INTRODUCTION

Stem cells are a class of multipotent undifferentiated cells, able to give rise to all cells in a particular tissue, organ or organism. A new subpopulation of stem cells was suggested to exist in tumors This hypothesis originated based on the recurrent clinical course of most cancers, as well as their self-renewal ability and uninhibited growth pattern, two categorical markers of tumorigenesis. The heterogenic cellular composition of solid tumors, such as melanoma, further supported the existence of CSCs, thought to be responsible for cancer recurrence after therapy (Menaa et al, 2009) As their nomenclature implies, CSCs possess the ability to self-renew indefinitely, as well as the potential to differentiate into the different types of cells that form the tumor bulk.

Results

Findings

CONCLUSION AND FUTURE DIRECTIONS