Angiotensin-(1-7) inhibits tumor angiogenesis in human lung cancer xenografts with a reduction in vascular endothelial growth factor

• Published in: Molecular cancer therapeutics Vol. 8; no. 6; pp. 1676 - 1683
• Main Authors: Soto-Pantoja, David R, Menon, Jyotsana, Gallagher, Patricia E, Tallant, E Ann
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.06.2009
• Subjects: angiogenesis; angiotensin; Angiotensin I - administration & dosage; Angiotensin I - pharmacology; angiotensin-(1-7); Animals; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane - blood supply; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - physiology; human xenograft; Humans; Injections, Subcutaneous; lung cancer; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; lung tumor; Mice; Mice, Nude; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - prevention & control; Neovascularization, Physiologic - drug effects; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Reverse Transcriptase Polymerase Chain Reaction; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-09-0161

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous seven-amino acid peptide hormone with antiproliferative properties. Our previous studies showed that Ang-(1-7) inhibits the growth of human lung cancer cells in vitro and reduces the size of human lung tumor xenografts in vivo . In the current study, s.c. injection of Ang-(1-7) not only caused a significant reduction in human A549 lung tumor growth but also markedly decreased vessel density, suggesting that the heptapeptide inhibits angiogenesis to reduce tumor size. A decrease in human endothelial cell tubule formation in Matrigel was observed following a 16 h incubation with Ang-(1-7), with a maximal reduction at a 10 nmol/L concentration. Ang-(1-7) had similar antiangiogenic effects in the chick chorioallantoic membrane, causing a >50% decrease in neovascularization. The Ang-(1-7)-induced reduction in both endothelial cell tubule formation and vessel formation in the chick was completely blocked by the specific Ang-(1-7) receptor antagonist [ d -proline 7 ]-Ang-(1-7), suggesting that these biological actions are mediated by an AT (1-7) receptor. Ang-(1-7) significantly reduced vascular endothelial growth factor-A protein and mRNA in tumors from mice treated with the heptapeptide compared with saline controls as well as in the parent A549 human lung cancer cells in culture. These results suggest that Ang-(1-7) may attenuate tumor angiogenesis by reducing vascular endothelial growth factor-A, a primary proangiogenic protein. Taken together, this study shows that Ang-(1-7) exhibits significant antiangiogenic activity and may be a novel therapeutic agent for lung cancer treatment targeting a specific AT (1-7) receptor. [Mol Cancer Ther 2009;8(6):1676–83]