Non-canonical NOTCH3 signalling limits tumour angiogenesis

Nat Commun. 2017 Jul 18;8:16074. doi: 10.1038/ncomms16074.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Animals
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Cell Death
  • Endothelial Cells / metabolism*
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Jagged-1 Protein / metabolism
  • Lung Neoplasms / metabolism*
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic*
  • Receptor, Notch3 / metabolism*

Substances

  • Jagged-1 Protein
  • Receptor, Notch3
  • Amyloid Precursor Protein Secretases