Key Points
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Notch signalling can be either oncogenic or tumour suppressive depending on the tissue and/or cellular context.
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Notch signalling is tumour suppressive for various solid tumours, including squamous cell carcinoma in several epithelial tissues, subtypes of brain cancer, liver cancer and small-cell lung cancer.
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Loss of Notch signalling can result in perturbed regulation of cell fate decisions in stem and progenitor cells, resulting in tumour development.
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Loss of Notch signalling can also lead to stromal remodelling and the generation of a pro-tumorigenic microenvironment that promotes carcinogenesis.
Abstract
The Notch signalling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues. The cellular processes and events that it controls are diverse, and continued investigation over recent decades has revealed how the role of Notch signalling is multifaceted and highly context dependent. Consistent with the far-reaching impact that Notch has on development and homeostasis, aberrant activity of the pathway is also linked to the initiation and progression of several malignancies, and Notch can in fact be either oncogenic or tumour suppressive depending on the tissue and cellular context. The Notch pathway therefore represents an important target for therapeutic agents designed to treat many types of cancer. In this Review, we focus on the latest developments relating specifically to the tumour-suppressor activity of Notch signalling and discuss the potential mechanisms by which Notch can inhibit carcinogenesis in various tissues. Potential therapeutic strategies aimed at restoring or augmenting Notch-mediated tumour suppression will also be highlighted.
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Acknowledgements
The work in the authors' laboratory is supported in part by the Swiss National Science Foundation and the Swiss Cancer League.
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Glossary
- γ-Secretase
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A multi-protein complex mediating the proteolytic S3 cleavage of Notch receptors upon ligand binding, thereby liberating the intracellular domain of Notch. The complex consists of presenilin 1, presenilin 2, nicastrin, anterior pharynx-defective 1 (APH1) and presenilin enhancer 2 (PEN2).
- DMBA–TPA mouse model of cutaneous chemical carcinogenesis
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A two-stage chemical skin carcinogenesis model that uses a single dose of the genotoxic carcinogen DMBA followed by multiple doses of a non-genotoxic tumour promoter, TPA.
- Field change
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The molecular alteration of large areas or groups of cells in a tissue. The molecular aberrations acquired are usually induced by prolonged injurious events and predispose to neoplasia and carcinogenesis.
- MLL–AF9
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An oncogene generated by the chromosomal translocation t(9;11) (p22;q23). This results in the in-frame fusion of mixed lineage leukaemia (MLL) with AF9. The transcripts produced from this fusion promote the development of myeloid leukaemias.
- Atopic dermatitis
-
An inflammatory skin disorder that is believed to be an immune hypersensitive response to environmental stimuli. Evidence supports a genetic basis for the disease.
- Metaplasia
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A change in the cell type that populates a given tissue, resulting in abnormal architecture, morphology and function.
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Nowell, C., Radtke, F. Notch as a tumour suppressor. Nat Rev Cancer 17, 145–159 (2017). https://doi.org/10.1038/nrc.2016.145
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DOI: https://doi.org/10.1038/nrc.2016.145
