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.
Highlights
Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway
The well-described so-called ‘canonical pathway’ depends on a strictly controlled proteolytic cascade induced by ligand binding: an S2 cleavage by metalloproteases followed by an S3 cleavage mediated by a presenilin-g-secretase complex
Notch signalling is a major regulator of angiogenesis as Dll4-mediated Notch activation controls the expression of the VEGF receptors (VEGFRs) and limits endothelial cells sprouting and proliferation[7,8]
Summary
Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Anti-ligand approaches such as anti-Dll[4] treatments produces non-productive angiogenesis through increased endothelial cells sprouting[14] These paradoxical observations could suggest that the role of Notch in tumour angiogenesis cannot be completely explained by canonical Notch signalling. 20) or the Hedgehog receptors Ptc and CDON21,22 share the ability to actively transduce a death signal in settings of ligand limitation, creating a state of cellular dependence to the presence of ligand for cell survival This pro-apoptotic activity has been proposed to act as a negative constrain for tumour progression by controlling cancer cell death[23,24]. We propose here that Notch[3] by acting as a dependence receptor in endothelial cells regulate tumour angiogenesis by regulating endothelial cell death
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