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Review
. 2008 Sep 1;27(38):5132-7.
doi: 10.1038/onc.2008.227.

Notch signaling regulates tumor angiogenesis by diverse mechanisms

J Dufraine  1 , Y Funahashi, J Kitajewski
Affiliations
Review

Notch signaling regulates tumor angiogenesis by diverse mechanisms

J Dufraine et al. Oncogene. .

Abstract

The Notch signaling pathway is fundamental to proper cardiovascular development and is now recognized as an important player in tumor angiogenesis. Two key Notch ligands have been implicated in tumor angiogenesis, Delta-like 4 and Jagged1. We introduce the proteins and how they work in normal developing vasculature and then discuss differing models describing the action of these Notch ligands in tumor angiogenesis. Endothelial Dll4 expression activates Notch resulting in restriction of new sprout development; for instance, in growing retinal vessels. In agreement with this activity, inhibition of Dll4-mediated Notch signaling in tumors results in hypersprouting of nonfunctional vasculature. This Dll4 inhibition may paradoxically lead to increased angiogenesis but poor tumor growth because the newly growing vessels are not functional. In contrast, Jagged1 has been described as a Notch ligand expressed in tumor cells that can have a positive influence on tumor angiogenesis, possibly by activating Notch on tumor endothelium. A novel Notch inhibitor, the Notch1 decoy, which blocks both Dll4 and Jagged1 has been recently shown to restrict tumor vessel growth. We discuss these models and speculate on therapeutic approaches.

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Figures

Figure 1
Figure 1
This figure explains angiogenic progression. Progression starts with degradation of extracellular matrix (ECM), and followed by survival and budding of activated endothelial cell, migration and proliferation. By recruiting smooth muscle cell (SMC), such as pericytes, maturation proceeds.
Figure 2
Figure 2
This figure schematizes where Dll4 and Notch are expressed during steps of sprouting angiogenesis.
See this image and copyright information in PMC

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MeSH terms