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.
Highlights
Neuroblastoma (NB) is a paediatric solid tumour arising from the neural crest (NC) during sympathetic nervous system (SNS) development [1]
Single cell sequencing data from the developing mouse sympathoadrenal lineage has allowed the elucidation of the cellular compartments presenting high levels of Hif-2α [53]. This analysis suggests that HIF-2α expression is generally high in chromaffin differentiated cells and in low risk, MYCN nonamplified tumours, precluding its consideration as an oncogene in NB
Hypoxia and Metastasis in Neuroblastoma In NB, metastatic disease is detected in approximately 50% of patients at diagnosis, frequently in the regional lymph nodes, bone marrow and bone [72]
Summary
Neuroblastoma (NB) is a paediatric solid tumour arising from the neural crest (NC) during sympathetic nervous system (SNS) development [1]. NB is the most common malignant extracranial solid tumour in children, and it is the cause of 10% of total child cancer deaths [3]. This cancer is characterised by great heterogeneity, including some very aggressive metastatic tumours which present poor response against conventional therapies and frequent relapses [4]. Local or systemic low oxygen exposure (hypoxia) has been linked to NC development, including neural crest cells (NCCs) migration and differentiation. We make an overview of the tools available for the study of this phenomenon and provide insights into possible therapeutic approaches under development
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