Endothelial Tie1 regulates tumor angiogenesis, vascular abnormalization and metastatic dissemination

Abstract

The Angiopoietin/Tie system is one of the most important vascular-tissue specific signaling pathways, essential during embryonic vascular development and maturation, and key regulator of adult homeostasis. The Tie receptors, Tie1 and Tie2, and their secreted angiopoietin (Ang) ligands, Ang1 and Ang2, have been identified as the main factors of the system. Ang1 is primarily produced by perivascular cells and acts in a paracrine fashion as strong Tie2 agonist that mediates endothelial cell (EC) survival and maturation signals. Ang2, expressed and stored in EC, functions primarily as an antagonist of Tie2 and promotes vascular destabilization. Nevertheless, it can act as a partial agonist of Tie2 in a context-dependent manner. Tie1 and Tie2 are both expressed by EC and share high similarities in their overall domain structure. Whereas Tie2 acts as the primary signal transducing receptor, Tie1 function as a holoreceptor is not completely understood: It does not activate signaling pathways on its own but rather modulates the Tie2 kinase activity. Tie1 is highly expressed in activated endothelial cells during embryogenesis and during pathological conditions, such as tumor progression and metastasis, but it is downregulated in the adult quiescent endothelium. Thus, Tie1 global deficiency in mice leads to embryonic lethality at late gestation due to perturbed vessel integrity, while its specific deletion in the growing tumor vasculature results in decreased blood vessel density. The combination of high expression in the tumor endothelium and low expression in the adult vasculature makes Tie1 an interesting molecule and a potential therapeutic target. Angiogenesis is one of the most critical steps during tumor growth and metastasis progression. Comparative tumor and metastasis experiments in wildtype and Tie1 endothelial-deficient mice were performed to mechanistically unravel the role of the orphan receptor during individual steps of tumor progression and metastasis. Analysis of the tumor vasculature demonstrated that Tie1 endothelial deletion induces no significant changes in the early steps of tumor growth but rather affects later steps of tumor progression. Endothelial-Tie1 deletion induces progressively normalization of primary tumor blood vessels accompanied by decreased microvessel density, increased mural cell coverage, improved vessel perfusion and reduced tumor cell intravasation into the blood stream as well as extravasation at secondary sites. These effects result in almost complete inhibition of post-surgical spontaneous lung metastasis and improved overall survival of Tie1-endothelial deleted mice. Mechanistically, Tie1 targeting in the primary tumor leads to vascular normalization and stabilization by increasing the proportion of Tie2-positive endothelial cells (stalk cells) and by potentiating the Ang1/Tie2 signaling axis which is primarily essential for the maintenance of endothelial quiescence and survival. The data establish a remarkable contribution of the orphan receptor Tie1 to primary tumor angiogenesis and to individual steps of metastatic cascade. These findings contribute to the mechanism-guided validation of Tie1 as a therapeutic target to sharpen the balance between triggering vascular regression and promoting vascular normalization.