The "neuro" of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder

Abstract

Neuroblastoma is a childhood cancer derived from cells of neural crest origin. The hallmarks of its enigmatic character include its propensity for spontaneous regression under some circumstances and its association with paraneoplastic opsoclonus, myoclonus, and ataxia. The neurodevelopmental underpinnings of its origins may provide important clues for development of novel therapeutic and preventive agents for this frequently fatal malignancy and for the associated paraneoplastic syndromes. Ann Neurol 2016;80:13-23.

Figure 1

Trunk neural crest cells: formation, migration pathways, and medial pathway derivatives. (A) Early in vertebrate development, neural crest cells (pink) form at the dorsal aspect of the neural tube (red) and migrate laterally or medially (black arrows). (B) Slightly later in development, some of the medially migrating neural crest cells differentiate into sympathoadrenal precursor cells (pink with green outline). These can give rise to mature sympathetic neurons (green), adrenal chromaffin cells (gray), and Schwann cells (purple). (C) In mature vertebrates, the sympathetic ganglia contain sympathetic neurons. The adrenal medulla, a sympathetic ganglion-like structure, contains adrenal chromaffin cells. Schwann cells reside in sympathetic ganglia and dorsal root ganglia, and populate all spinal nerves. Schwann-like satellite cells associate with sympathetic and dorsal root ganglia. The adrenal medulla also contains Schwann-like cells.

Figure 2

Mechanisms of neuroblastoma regression. Shown are the major mechanisms that have been proposed to explain the phenomenon of neuroblastoma regression in infants. Three of the mechanisms (telomere shortening, TrkA-mediated apoptosis in the absence of NGF, and epigenetic changes) likely lead to apoptosis and programmed cell death. However, cellular or humoral immune response to tumor antigens would likely lead to direct, immune-mediated killing of neuroblastoma cells. NGF = nerve growth factor; TrkA = Trk receptor tyrosine kinase A.

Figure 3

B-cell and T-cell involvement in the pathogenesis of opsoclonus-myoclonus-ataxia syndrome (OMAS) in neuroblastoma. OMAS is thought to be a consequence of the cross-reaction of a neuroblastoma antigen with proteins in the cerebellum and brainstem. Both cytokine-stimulated B-cell generation of antibodies and T-cell cytotoxicity are thought to be involved.

Figure 4

Proposed targets for neuroblastoma therapy. Proposed and experimental targeted therapy for neuroblastoma has been aimed at compounds on the cell surface (GD2; ALK; neurotrophin receptors; neurotransmitter uptake systems; Kidins220), in nuclear and mitochondrial membranes (retinoic acid receptor; Bcl-2), in the cytoplasm (PRMT1/EYA/SIX), and in the nucleus (MYCN). Therapy for opsoclonus-myoclonusataxia syndrome is aimed at the immune mechanisms through which it is thought to arise. ALK = anaplastic lymphoma kinase; Bcl-2 = B-cell lymphoma 2; EYA = eyes absent; GD2 = disialganglioside 2; MYCN = N-Myc; PRMT1 = protein arginine methyl-transferase type I; SIX = sine oculis.