Angiopoietin-2 Functions as a Tie2 Agonist in Tumor Models, Where It Limits the Effects of VEGF Inhibition

Abstract

The angiopoietins Ang1 (ANGPT1) and Ang2 (ANGPT2) are secreted factors that bind to the endothelial cellspecific 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. Cancer Res; 73(1); 108-18. Ó2012 AACR.

T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle

“…Shyu et al (2003) reported that the variations in the expression of Ang2 and Tie2 have a temporal pattern with a maximal increase at 24-48 h after reperfusion. The most validated model explaining Ang2 role in tumors and in cardiac capillary density modifications proposes that Ang2 inhibits Tie2 signaling facilitating VEGF-dependent angiogenesis (Maisonpierre et al 1997, Daly et al 2013. As in our model Ang2 expression was not associated with VEGF expression, our findings do not suggest that Ang2 and VEGF act in concert in response to T 3 infusion in I/R.…”

“…More precisely, Ang2 is present at low levels in resting endothelial cells, whereas it is increased in the endothelial cells of remodeling blood vessels (Maisonpierre et al 1997, Daly et al 2013. Furthermore, Ang2 expression is upregulated in a wide range of human cancers , Daly et al 2013) and Tie2 receptor is broadly expressed in the endothelium of quiescent adult vasculature.…”

“…More precisely, Ang2 is present at low levels in resting endothelial cells, whereas it is increased in the endothelial cells of remodeling blood vessels (Maisonpierre et al 1997, Daly et al 2013. Furthermore, Ang2 expression is upregulated in a wide range of human cancers , Daly et al 2013) and Tie2 receptor is broadly expressed in the endothelium of quiescent adult vasculature. In contrast to Ang2, Ang1, which is expressed primarily in smooth muscle cells and other perivascular cells, seems to promote, through its Tie2 receptor activation, blood vessel maturation and stabilization (Davis et al 1996, Thurston et al 2000).…”

Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway

“…Receptor tyrosine kinases act as potent oncoproteins and are abnormally expressed in a number of cancer types, including gliomas (5). Angiopoietin-1 (Ang1) receptor (TEK, also known as Tie2) is a receptor tyrosine kinase that was identified as an endothelial-cell-specific receptor with a critical role in the modulation of vasculogenesis and remodeling (6). Tie2 expression occurs, and is partially maintained, during differentiation in human neural stem cells (7), but not in mature neurons (8).…”

“…Ang1 is a secreted ligand for Tie2 that maintains vascular plasticity, perturbations in which can contribute to abnormal vascular growth (4). Daly et al (6) revealed that Ang2 functions as a Tie2 agonist in tumor models, limiting the effects of VEGF inhibition (6). Mitsutake et al (13) revealed that Tie-2 and its ligand Ang1 were expressed in benign and malignant human thyroid tumor cells, as well as in hyperplastic regions of adenomatous goiter (13).…”