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  • Review Article
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Notch signalling in solid tumours: a little bit of everything but not all the time

Nature Reviews Cancer volume 11, pages 338–351 (2011)Cite this article

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Key Points

  • A causative role for Notch signalling is well established in T cell acute lymphoblastic leukaemias (T-ALLs), which have activating mutations in the Notch genes resulting in a constitutively active pathway. By contrast, solid tumours, which have ample opportunity to activate the pathway, exhibit inappropriate activation by multiple mechanisms, such as overexpression of ligand or loss of negative regulators of the pathway.

  • The role of Notch signalling in solid tumours is highly dependent on the spatial and temporal context of Notch activation, as well as the status of other signalling pathways in the cells.

  • Notch signalling has opposing roles in tumorigenesis depending on the cell type. Opposite interactions of the Notch pathway have been documented with the WNT and p53 pathways. Although synergy with WNT and antagonism of the p53 pathway directs the oncogenic role of Notch, the opposite is seen in the tumour suppressor context.

  • Notch signalling has a major role in the maintenance and progression of tumours by promoting epithelial to mesenchymal transition (EMT) and angiogenesis. It also confers resistance to radiation and chemotherapeutic agents.

  • The knowledge of the extensive crosstalk of the Notch pathway with other pathways such as the epidermal growth factor receptor (EGFR) pathway could prove useful in developing combinatorial cancer therapies.

Abstract

The discovery of Notch in Drosophila melanogaster nearly a century ago opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by Notch signalling. As would be expected with such a pleiotropic pathway, the deregulation of Notch signalling leads to several pathological conditions, including cancer. A role for Notch is well established in haematological malignancies, and more recent studies have provided evidence for the importance of Notch activity in solid tumours. As it is thought to act as an oncogene in some cancers but as a tumour suppressor in others, the role of Notch in solid tumours seems to be highly context dependent.

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Figure 1: Structural organization and proteolytic processing of the Notch receptor.
Figure 2: Signal transduction from Notch receptors and ligands.
Figure 3: Oncogenic and tumour suppressive interactions of Notch.
Figure 4: Notch-regulated tumour–microenvironment interactions in tumour maintenance and progression.

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Acknowledgements

The authors would like to thank members of the Capobianco laboratory for support and D. Robbins and J. Diez for critical reading of the manuscript and useful suggestions. Work in the authors' laboratory is partly supported by grants from the US National Cancer Institute (ROI CA 83736) and the Samuel Waxman Foundation for Cancer Research, USA. The authors sincerely apologize to all their colleagues whose work has not been referenced in this article.

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  1. DeWitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, Molecular Oncology Program, University of Miami Miller School of Medicine, Florida, 33136, USA

    Prathibha Ranganathan, Kelly L. Weaver & Anthony J. Capobianco

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  1. Prathibha Ranganathan
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  2. Kelly L. Weaver
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Correspondence to Anthony J. Capobianco.

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Glossary

Negative selection

The intrathymic elimination of CD4+CD8+ thymocytes that express T cell receptors with high affinity for self antigens.

Type I transmembrane receptors

Proteins that span the plasma membrane once, with the carboxy-terminal end extending into the cytoplasm.

Exocrine pancreas

The portion of the pancreas that secretes digestive enzymes that are then passed on to the small intestine.

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Ranganathan, P., Weaver, K. & Capobianco, A. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer 11, 338–351 (2011). https://doi.org/10.1038/nrc3035

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