Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy

Abstract

The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy.

Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

“…Conditional deletion of Tie1 in ECs at different stages of primary tumor growth and metastasis confirmed the previously reported antiangiogenic effect of EC Tie1 deletion (22) and enabled beyond that the temporal analysis of Tie1 effects on tumor Mechanistically, the contribution of Tie1 to Tie2 signaling is still poorly understood. Because Tie1 is not ligand binding, it has been hypothesized that Tie1 contributes to Tie2 signaling by heterodimerization via interaction of the fibronectin type III domain n3 (9) and/or by affecting the binding of the angiopoietin ligands to Tie2 (21,(37)(38)(39).…”

“…Functionally, Tie1 acts as a contextual regulator of Tie2, as it counterregulates Tie2 in angiogenic tip cells and sustains Tie2 signaling in remodeling stalk cell vasculature (21). As a result, conditional postnatal deletion of Tie1 in ECs results in reduced retinal vascularization, with increased EC apoptosis and induced vascular regression (21,22). In adult mice, the Tie1 ectodomain is cleaved during inflammation, leading to reduced Tie2 phosphorylation and downregulated Tie2 expression in an Ang2-dependent manner.…”

“…Tie1 is functionally involved in important vascular pathologies, including atherosclerosis and tumor angiogenesis (22,25). It has long been known that Tie1 is prominently upregulated in the intratumoral vasculature (26)(27)(28)(29)(30), but its functional contribution to tumor progression has only recently been explored.…”

“…In contrast to the Tie2 ligand Ang2, the orphan receptor Tie1 has been much less studied in the context of tumor angiogenesis (22). Like Ang2, Tie1 is transcriptionally strongly upregulated in the angiogenic vasculature and downregulated in resting ECs (21,26,27,29,30,35).…”

“…al EC Tie1 deletion in adult mice was shown to inhibit angiogenesis, resulting in reduced tumor growth. This is associated with increased Notch pathway activity and results in improved angiopoietin antagonist therapy (22). Building on this seminal work, the present study was aimed at mechanistically dissecting the role of Tie1 during primary tumor growth and elucidating its contribution to metastatic progression.…”