Abstract
Neuroblastoma is a common extracranial solid tumour of childhood, responsible for 15% of cancer-related deaths in children. Prognoses vary from spontaneous remission to aggressive disease with extensive metastases, where treatment is challenging. Tumours are thought to arise from sympathoadrenal progenitor cells, which derive from an embryonic cell population called neural crest cells that give rise to diverse cell types, such as facial bone and cartilage, pigmented cells, and neurons. Tumours are found associated with mature derivatives of neural crest, such as the adrenal medulla or paraspinal ganglia. Sympathoadrenal progenitor cells express anaplastic lymphoma kinase (ALK), which encodes a tyrosine kinase receptor that is the most frequently mutated gene in neuroblastoma. Activating mutations in the kinase domain are common in both sporadic and familial cases. The oncogenic role of ALK has been extensively studied, but little is known about its physiological role. Recent studies have implicated ALK in neural crest migration and sympathetic neurogenesis. However, very few downstream targets of ALK have been identified. Here, we describe pathological activation of ALK in the neural crest, which promotes proliferation and migration, while preventing differentiation, thus inducing the onset of neuroblastoma. Understanding the effects of ALK activity on neural crest cells will help find new targets for neuroblastoma treatment.
Highlights
These cells most likely originate from sympathoadrenal progenitor cells, which derive from neural crest cells
anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first identified in anaplastic large cell lymphoma patients, where ALK translocations led to an aberrant fusion protein with nucleophosmin (NPM)
Despite many decades of work, the cell of origin of neuroblastoma has not been clearly defined; it is generally accepted that neuroblastoma arises from trunk neural crest cells contributing to the sympathoadrenal lineage
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Tumours are found along the peripheral nervous system and are composed of undifferentiated neuroblastic cells These cells most likely originate from sympathoadrenal progenitor cells, which derive from neural crest cells. High-risk disease represents approximately 40% of all diagnoses [1,2] This depends on the age of the child (>15-month-old children display poorer prognosis), and on the stage and the genetic makeup of the tumour [3]. PHOX2B encodes a transcription factor essential for autonomic nervous system development, where it functions in sympathoadrenal specification, supporting the idea that neuroblastoma arises due to pathological development in this neural-crest-derived lineage [6]. In 1997, transgenic overexpression of MYCN in neural crest cells was shown to cause neuroblastoma in mice, helping to clarify the role of MYCN in the genesis of this disease [12]. We will summarise the current understanding of ALK function and consider its potential role in neural crest development and in the onset of neuroblastoma tumorigenesis
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