Editors' ChoiceCancer

A notch against cancer

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Science Translational Medicine  03 Feb 2016:
Vol. 8, Issue 324, pp. 324ec17
DOI: 10.1126/scitranslmed.aaf2004

Notch signaling has been shown to be protumorigenic in both laboratory studies and clinical studies of solid tumors. The evidence was compelling enough for Notch inhibitors to be evaluated in clinical trials. The hope has been that Notch inhibitors would decrease resistance to chemotherapy by targeting Notch-mediated proliferation and angiogenesis pathways. However, the clinical trials of Notch inhibitors in melanoma have not been successful, and a recent study explains why.

Work by Bonyadi Rad et al. demonstrated an unexpected role for Notch4 as a tumor suppressor in melanoma. The group showed that overexpression of a constitutively active intracellular domain of Notch4 decreased the proliferation and invasiveness of melanoma cells. In mice, tumor cell overexpression of the Notch4 active domain markedly delayed tumor development. The tumor suppressive mechanism reported in this study was Notch4-mediated promotion of a mesenchymal to epithelial transition (MET) in both morphology and gene expression. The mouse findings were confirmed in human melanomas, in which high Notch4 staining correlated with high E-cadherin staining. The researchers also identified a mechanism by which Notch promotes MET with its downstream targets, Hey1 and Hey2, being direct transcriptional repressors of epithelial to mesenchymal transition genes, Snail2 and Twist1.

Although Notch inhibition has had some success in clinical trials with some cancers, in melanoma and squamous cancers Notch signaling has shown antitumorigenic effects. This latest study is a reminder that different tumor types have distinct properties and that some paradoxical pathways may be drug targets in some cancers but antitumorigenic in others. The question that remains to be answered is whether Notch inhibition in cancers that do not respond to this therapy actually promotes malignant behavior.

E. Bonyadi Rad et al., Notch4 signaling induces a mesenchymal-epithelial-like transition in melanoma cells to suppress malignant behaviors. Cancer Res. 10.1158/0008-5472.CAN-15-1722 (2016). [Abstract]

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