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Nerves in gastrointestinal cancer: from mechanism to modulations

Abstract

Maintenance of gastrointestinal health is challenging as it requires balancing multifaceted processes within the highly complex and dynamic ecosystem of the gastrointestinal tract. Disturbances within this vibrant environment can have detrimental consequences, including the onset of gastrointestinal cancers. Globally, gastrointestinal cancers account for ~19% of all cancer cases and ~22.5% of all cancer-related deaths. Developing new ways to more readily detect and more efficiently target these malignancies are urgently needed. Whereas members of the tumour microenvironment, such as immune cells and fibroblasts, have already been in the spotlight as key players of cancer initiation and progression, the importance of the nervous system in gastrointestinal cancers has only been highlighted in the past few years. Although extrinsic innervations modulate gastrointestinal cancers, cells and signals from the gut’s intrinsic innervation also have the ability to do so. Here, we shed light on this thriving field and discuss neural influences during gastrointestinal carcinogenesis. We focus on the interactions between neurons and components of the gastrointestinal tract and tumour microenvironment, on the neural signalling pathways involved, and how these factors affect the cancer hallmarks, and discuss the neural signatures in gastrointestinal cancers. Finally, we highlight neural-related therapies that have potential for the management of gastrointestinal cancers.

Key points

  • The gut is a highly innervated, dynamic ecosystem wherein nerves are key for intestinal functioning and homeostasis by communicating with a variety of cell types and the gut microbiome.

  • Neural contributions to gastrointestinal cancers represent a flourishing area of investigation as both intrinsic and extrinsic nerves influence gastrointestinal tumorigenesis via their interplay with cancer cells.

  • Neural-related signals and pathways can influence the cancer hallmarks, interfering with several cancer cell characteristics (metabolism and (epi)genomic stability) and/or supporting a cancer-promoting microenvironment (immune infiltration, extracellular matrix).

  • While neoneurogenesis and axonogenesis are emerging within the gastrointestinal cancer field, both topics require in-depth investigation to identify their exact origin and driving mechanisms.

  • Cancer cells are able to hijack (embryonic) neural pathways to promote their own fitness.

  • Targeting neural cell-derived messengers and their respective receptors holds great promise in the treatment of gastrointestinal cancers.

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Fig. 1: Nervous signalling paths and modulators of the gastrointestinal tract in mammals.
Fig. 2: Cholinergic signalling in gastrointestinal cancers.
Fig. 3: Adrenergic signalling in gastrointestinal cancers.
Fig. 4: Neural-related factors alter the epigenome in gastrointestinal cancer cells.

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Acknowledgements

The authors’ work is financially supported by VENI-NWO grant (016.186.124) obtained by V.M., the Kootstra Talent Fellowship grant (Maastricht University) obtained by N.V. and the Hestia – NWO grant (VidW.1154.18.045) obtained by M.I and V.M.

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Vaes, N., Idris, M., Boesmans, W. et al. Nerves in gastrointestinal cancer: from mechanism to modulations. Nat Rev Gastroenterol Hepatol 19, 768–784 (2022). https://doi.org/10.1038/s41575-022-00669-9

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