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Mechanisms of neuroblastoma regression

Nature Reviews Clinical Oncology volume 11, pages 704–713 (2014)Cite this article

Subjects

Key Points

  • Neuroblastomas in younger children have a higher propensity to undergo spontaneous regression than any other human malignancy, but only genetic subtype 1 tumours with numerical chromosome aberrations are prone to spontaneous regression

  • Although spontaneous regression of neuroblastoma is strongly associated with stage 4S disease, mass-screening studies suggest that genetic subtype 1 tumours of any stage in infants <18 months can undergo spontaneous regression

  • The TrkA/NGF pathway might have a major role in causing spontaneous regression, but alternative mechanisms might involve cellular or humoral immune responses, telomere shortening, or epigenetic modifications

  • Inhibition of the TrkA pathway represents the most-promising approach to initiate regression in infants with favourable tumours; other approaches involving immune modulation or epigenetic regulation are being investigated

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.

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Figure 1: Genomic model of neuroblastoma development.
Figure 2: Mechanisms of spontaneous regression.

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Acknowledgements

This work was supported in part by NIH grants R01-CA094194 and R01-039,771; Alex's Lemonade Stand Foundation; and the Audrey E. Evans endowed chair (G.M.B.).

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  1. Division of Oncology, The Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, 19104-4302, PA, USA

    Garrett M. Brodeur & Rochelle Bagatell

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G.M.B. and R.B. researched data and discussed content for article, wrote, reviewed and edited the manuscript before submission.

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Brodeur, G., Bagatell, R. Mechanisms of neuroblastoma regression. Nat Rev Clin Oncol 11, 704–713 (2014). https://doi.org/10.1038/nrclinonc.2014.168

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