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Notch signalling in solid tumours: a little bit of everything but not all the time
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Journal Article
Notch signalling in solid tumours: a little bit of everything but not all the time
2011
Overview
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.
The Notch family of receptors activate a complex web of cancer-relevant signalling pathways, and activating mutations in
NOTCH1
are common drivers of T cell acute lymphoblastic leukaemia (T-ALL). Despite this oncogenic role of NOTCH1 in T-ALL, mutations in Notch genes are rare in solid cancers. This Review discusses the growing evidence that deregulation of Notch signalling can indeed have a major role in the development of various solid tumours, and the oncogenic versus tumour suppressive roles of Notch signalling are highly context dependent.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
