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 β-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 β 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 β-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.