Hypoxia in the Initiation and Progression of Neuroblastoma Tumours

Abstract

Neuroblastoma is the most frequent extracranial solid tumour in children, causing 10% of all paediatric oncology deaths. It arises in the embryonic neural crest due to an uncontrolled behaviour of sympathetic nervous system progenitors, giving rise to heterogeneous tumours. Low local or systemic tissue oxygen concentration has emerged as a cellular stimulus with important consequences for tumour initiation, evolution and progression. In neuroblastoma, several evidences point towards a role of hypoxia in tumour initiation during development, tumour cell differentiation, survival and metastatic spreading. However, the heterogeneous nature of the disease, its developmental origin and the lack of suitable experimental models have complicated a clear understanding of the effect of hypoxia in neuroblastoma tumour progression and the molecular mechanisms implicated. In this review, we have compiled available evidences to try to shed light onto this important field. In particular, we explore the effect of hypoxia in neuroblastoma cell transformation and differentiation. We also discuss the experimental models available and the emerging alternatives to study this problem, and we present hypoxia-related therapeutic avenues being explored in the field.

Keywords: cancer stem cells; hypoxia; neural crest cells; neuroblastoma; paediatric oncology.

Figure 1

Experimental approaches for the study of hypoxia in neuroblastoma. Connecting molecular characterisation with information directly obtained from in vivo assays in hypoxia chambers and/or in vitro cultured spheroids would allow the generation of relevant evidence-driven hypothesis. 3D systems can be used for ex vivo or in vitro testing. Decreased oxygen concentration is symbolized in the illustration as red arrow pointing down or color gradient blue to red. Green arrows denote possible workflows.

Figure 2

Effects of hypoxia in NB initiation and progression. (A) Neural crest (NC) migrating cells can undergo malignant transformation due to hypoxia exposition or disregulation, driving tumourigenesis. (B) A neuroblastoma (NB) tumour is comprised of phenotypically divergent cells. Hypoxia might favour malignant progression in NB tumours, characterised by the activation of angiogenesis, alteration of cellular differentiation, tumour cell survival and resistance and an increase of metastasis. The extracellular matrix is also affected by hypoxia. NB: neuroblastoma; NCC: neural crest cell; ADR: adrenergic cells, MES: mesenchymal undifferentiated cells; TPC: Undifferentiated tumour-propagating cells. Blue arrow in box denote an increase.