Angiopoietin-1 and -2 Exert Antagonistic Functions in Tumor Angiogenesis, yet Both Induce Lymphangiogenesis

Abstract

Members of the Angiopoietin family regulate various aspects of physiologic and pathologic angiogenesis. Although Angiopoietin-1 (Ang-1) decreases endothelial cell permeability and increases vascular stabilization via recruitment of pericytes and smooth muscle cells to growing blood vessels, Angiopoietin-2 (Ang-2) mediates angiogenic sprouting and vascular regression. In this study, we used the Rip1Tag2 transgenic mouse model of pancreatic b-cell carcinogenesis to investigate the roles of Ang-1 and Ang-2 in tumor angiogenesis and tumor progression. On their own, transgenic expression of human Ang-1 or Ang-2 in pancreatic b cells caused formation of peri-insular lymphatic vessels in the absence of effects on blood vessel density, islet morphology, or physiology. When crossed to Rip1Tag2 mice, both Ang-1-and Ang-2-expressing b-cell tumors showed increased peritumoral lymphangiogenesis in the absence of metastasis to local lymph nodes or distant organs. There was no alteration in tumor outgrowth, blood vessel density, or vessel maturation in Ang-1-expressing tumors. In contrast, Ang-2-expressing tumors exhibited diminished pericyte recruitment to blood vessels that were dilated, nonfunctional, and highly permeable. These tumors were hemorrhagic, highly infiltrated by leukocytes, and impaired in outgrowth. Together, our findings establish that Ang-2 antagonizes Ang-1 function, leading to excessive vessel sprouting with impaired pericyte recruitment and vessel stabilization. The poor perfusion of immature blood vessels results in retarded tumor growth, defining an important pathophysiologic pathway required for efficient tumorigenesis. Cancer Res; 71(17); 5717-27. Ó2011 AACR.

Harnessing developmental processes for vascular engineering and regeneration

“…TGFβ inhibits EC proliferation and stimulates mural cell differentiation into SMCs or perivascular cells, as well as affecting matrix deposition (Heimark et al, 1986;D'Amore and Smith, 1993). ANG1, which activates ligands for TIE2 (endothelial-specific receptor tyrosine kinase; TEK), is expressed by mural cells and stimulates mural coverage and basement membrane deposition, thereby promoting vessel tightness, whereas angiopoietin 2 (ANG2 or ANGPT2), which is an antagonist to ANG1 and TIE2 signaling, promotes mural cell detachment and EC sprouting, resulting in angiogenesis (Fagiani et al, 2011;Yu et al, 2013). Accumulating evidence demonstrates that stromal cell-derived factor 1 (SDF1) and insulin-like GF (IGF) stimulate angiogenesis through recruitment of EPCs from bone marrow and enhanced EPC mobilization (Maeng et al, 2009;Jujo et al, 2010).…”

Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment

“…Consistently, recombinant ANGPT1 protein and adenoviral vector-mediated overexpression of ANGPT1 were shown to induce lymphatic vessel sprouting and hyperplasia (Morisada et al 2005;Tammela et al 2005). The lymphangiogenic effect of ANGPT1 was also shown in a transgenic mouse model, where overexpression of ANGPT1 or ANGPT2 in pancreatic β-cells was shown to induce peri-insular lymphangiogenesis (Fagiani et al 2011). Both ANGPT1 and ANGPT2 bind to TIE-2, and TIE-2-mediated signaling is crucial for blood vascular maturation and the maintenance of its integrity (Augustin et al 2009).…”

Stimulated mast cells promote maturation of myocardial microvascular endothelial cell neovessels by modulating the angiopoietin-Tie-2 signaling pathway

“…While Ang-1 can activate Tie-2, Ang-2 has a similar affinity for Tie-2, but does not activate it, and competes with Ang-1 for Tie-2 binding. It has been shown that Ang-1 is an agonist for endothelial cells and that Ang-2 can act as a context-dependent antagonist (21). Studies demonstrated that Ang-1 is essential for vascular development by promoting blood vessel maturation (9), and by inhibiting vessel leakage, endothelial apoptosis, and microvascular regression (22).…”