Abstract
The angiopoietins Ang1 (ANGPT1) and Ang2 (ANGPT2) are secreted factors that bind to the endothelial cell-specific receptor tyrosine kinase Tie2 (TEK) and regulate angiogenesis. Ang1 activates Tie2 to promote blood vessel maturation and stabilization. In contrast, Ang2, which is highly expressed by tumor endothelial cells, is thought to inhibit Tie2 activity and destabilize blood vessels, thereby facilitating VEGF-dependent vessel growth. Here, we show that the inhibition of tumor xenograft growth caused by an Ang2-specific antibody (REGN910) is reversed by systemic administration of the Tie2 agonist Ang1. These results indicate that Ang2 blockade inhibits tumor growth by decreasing Tie2 activity, showing that Ang2 is a Tie2 activator. REGN910 treatment of tumors resulted in increased expression of genes that are repressed by Tie2 activation, providing further evidence that REGN910 inhibits Tie2 signaling. Combination treatment with REGN910 plus the VEGF blocker aflibercept reduced tumor vascularity and tumor perfusion more dramatically than either single agent, resulting in more extensive tumor cell death and more potent inhibition of tumor growth. Challenging the prevailing model of Ang2 as a destabilizing factor, our findings indicate that Ang2 plays a protective role in tumor endothelial cells by activating Tie2, thereby limiting the antivascular effects of VEGF inhibition. Thus, blockade of Ang2 might enhance the clinical benefits currently provided by anti-VEGF agents. .
Highlights
The Angiopoietin/Tie2 signaling system is essential for vascular development and function [1]
human umbilical vein endothelial cells (HUVEC) expressing elevated levels of Ang2 exhibited a marked increase in Tie2 phosphorylation (Fig. 1B, lane 2), which was completely inhibited by the addition of REGN910 at concentrations of 2 nmol/L or above (Fig. 1B, lanes 4–6), confirming that REGN910 inhibits autocrine Ang2-mediated Tie2 activation
The dominant model for Ang2 function in tumors proposes that Ang2 inhibits Tie2 signaling and destabilizes tumor blood vessels, thereby facilitating VEGF-dependent angiogenesis [1, 7, 13]
Summary
The Angiopoietin/Tie signaling system is essential for vascular development and function [1]. Tie is an endothelial cell– specific tyrosine kinase receptor for the angiopoietin ligands, the best studied of which are angiopoietin-1 (ANGPT1; Ang1) and angiopoietin-2 (ANGPT2; Ang). Ang is a strong Tie agonist that is produced primarily by perivascular cells, and Ang1/Tie signaling is believed to promote blood vessel maturation and stabilization [1,2,3,4,5,6]. Ang is produced primarily by the endothelial cells in remodeling blood vessels [1, 7, 8] and is believed to function largely as a Tie antagonist to promote tumor angiogenesis and inflammation [1, 7,8,9,10,11,12,13]. Ang expression is upregulated in a wide range of human cancers [14,15,16,17,18,19,20], and recent preclinical studies using Ang inhibitors and Ang knockout mice have established that Ang is important for tumor angiogenesis and tumor growth [21,22,23,24,25,26,27,28,29,30,31].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
