1. Non-canonical NOTCH3 signalling limits tumour angiogenesis
- Author
-
Lin, Shuheng, Negulescu, Ana, Bulusu, Sirisha, Gibert, Benjamin, Delcros, Jean-Guy, Ducarouge, Benjamin, Rama, Nicolas, Gadot, Nicolas, Treilleux, Isabelle, Saintigny, Pierre, Meurette, Olivier, and Mehlen, Patrick
- Subjects
Lung Neoplasms ,Cell Death ,Neovascularization, Pathologic ,Science ,Endothelial Cells ,Sciences bio-médicales et agricoles ,Article ,Mice, Inbred C57BL ,HEK293 Cells ,Carcinoma, Non-Small-Cell Lung ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Amyloid Precursor Protein Secretases ,Receptor, Notch3 ,Jagged-1 Protein - Abstract
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., info:eu-repo/semantics/published
- Published
- 2017