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Non-canonical NOTCH3 signalling limits tumour angiogenesis
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Journal Article
Non-canonical NOTCH3 signalling limits tumour angiogenesis
2017
Overview
Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells.
Notch signalling is deregulated in several cancers; therefore, strategies targeting this pathway are currently being explored. Here the authors report a pro-apoptotic function of Notch3 in endothelial cells; consequently, when Notch3 is silenced in stroma cells, tumour growth and angiogenesis are increased.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 96
/ 96/2
/ Amyloid Precursor Protein Secretases - antagonists & inhibitors
/ Animals
/ Cancer
/ Carcinoma, Non-Small-Cell Lung - metabolism
/ Endothelial Cells - metabolism
/ Human Umbilical Vein Endothelial Cells
/ Humanities and Social Sciences
/ Humans
/ Jagged-1 Protein - metabolism
/ Neovascularization, Pathologic
/ Receptor, Notch3 - metabolism
/ Rodents
/ Science
/ Stroma
/ Tumors
