Conditional expression of Ang‐2 during tumor angiogenesis: tightly balanced Angiopoietin/Tie2 signaling determines the tumor vascular phenotype

Angiopoietins play important roles in the formation of neovessels and complex vascular networks. Angiopoietin‐1 (Ang‐1) and Angiopoietin‐2 (Ang‐2) are both members of a family of growth factors which display opposing effects on the activation of the tyrosine kinase with Ig und EGF homology domain 2 (Tie2). To more precisely discriminate the antagonizing actions of Ang‐1 and Ang‐2 during tumor angiogenesis, we applied a transgenic animal model which allowed the inducible expression of Ang‐2 in endothelial cells and a mammary carcinoma model designed to express Ang‐1 and Ang‐2. When comparing the vascular morphology of Ang‐2 expressing mammary tumors in nude mice and lewis‐lung tumors in Ang‐2 transgenic mice, small blood vessels with apoptotic endothelial cells and pericyte denudation were evident. In addition, disrupted cell‐cell contacts were often observed. Consequently, we deteced increased vascular permeability by magnetic resonance imaging in Ang‐2 positive tumors, indicative for non‐functional and leaky blood vessels. Notably, high numbers of infiltrating monocytic cells expressing CD11b in Lewis lung tumors of Ang‐2 transgenic animals were also evident. The presence of infiltrating cells suggests a paracrine mechanism and indicates that growth factors secreted by monocytes/macrophages might be important to facilitate/promote angiogenesis in tumors.