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 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.
Highlights
The transition from prevascular hyperplasia to highly vascularized, outgrowing tumors is referred to as the "angiogenic switch" [1]
Transgenic expression of human Ang-1 and Ang-2 Quantitative reverse transcription PCR and immunoblotting analysis revealed that endogenous mouse Ang-1 and Ang-2 were expressed at low levels in the b cells of pancreatic islets of Langerhans or in tumors of RT2 mice
To assess whether angiopoietins could have a role in tumor angiogenesis in RT2 mice we targeted expression of human Ang-1 (hAng-1) and human Ang-2 (hAng-2) to the b cells of pancreatic islets of Langerhans. cDNA fragments encoding hAng-1 and hAng-2, fused in frame at their 50 ends with a signal peptide and a 10-amino acid Myc-tag were cloned between the rat insulin II gene promoter fragment Rip1 [19] and a SV40 polyadenylation site (Ref. 27; Supplementary Fig. S2B)
Summary
The transition from prevascular hyperplasia to highly vascularized, outgrowing tumors is referred to as the "angiogenic switch" [1]. The requirement of active angiogenesis for tumor outgrowth has been repeatedly shown, for example, by depletion of angiogenic growth factors or by the specific targeting of the activities of their receptors [2,3,4]. Many factors are involved in inducing tumor angiogenesis and, among them, members of the VEGF family, fibroblast growth factors (FGF), and several others have been extensively studied [2,3,4]. By binding to their cognate receptor Tie-2, angiopoietins (Ang) have been shown to exert critical roles during physiologic angiogenesis and tumor angiogenesis. Whereas Ang-3 and Ang-4, diverging gene counterparts of mice and human, respectively, are still poorly understood, Ang-1 and Ang-2
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