Mechanisms of neuroblastoma regression

Abstract

Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches.

Figure 1

Genomic model of neuroblastoma development. The major genomic pathways and genotype subsets of neuroblastoma are depicted here. Type 1 neuroblastomas have a favourable clinical outcome and consistently show numerical chromosome abnormalities (near-triploidy) without SCAs. They also have high expression of the TrkA neurotrophin receptor, and they are prone to undergo spontaneous regression (or differentiation), depending on the presence (+) or absence (−) of NGF in their microenvironment, respectively. Conversely, type 2 neuroblastomas are unfavourable clinically and are characterized by SCAs. Many of these tumours have unbalanced gain of chromosome 17q and express TrkB and BDNF. They can be separated into two subtypes based on additional genomic changes: type 2A tumours also have selective regional loss of 3p, 4p, and/or 11q, and many also have gain of chromosome 7; and type 2B have MYCN amplification, usually with 1p deletion, and they generally lack the additional changes found in type 2A. Type 2B tumours are the most aggressive and rapidly progressive subtype. Abbreviations: BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; SCA, segmental chromosomal abnormalities.

Figure 2

Mechanisms of spontaneous regression. Shown are the major pathways that have been proposed to explain the phenomenon of spontaneous regression. These include: neurotrophin deprivation (TrkA without NGF) and activation of developmentally programmed apoptosis (1); immune-mediated cell killing by anti-neuroblastoma antibodies (and antibody-dependent cellular toxicity) or by NK cells (2); telomere shortening and apoptosis triggered by low/absent levels of telomerase (3); and epigenetic changes in gene expression controlled by DNA methylation, histone modification, or alterations in chromatin remodelling (4). Abbreviations: NGF, nerve growth factor; NK, natural killer cells; TrkA, tropomyosin receptor kinase A.