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Angiotensin‐(1‐7) reduces proliferation and angiogenesis of human prostate cancer xenografts with a decrease in angiogenic factors and an increase in sFlt‐1
Author(s) -
Krishnan Bhavani,
Torti Frank M.,
Gallagher Patricia E.,
Tallant E. Ann
Publication year - 2013
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22540
Subject(s) - angiogenesis , prostate cancer , medicine , prostate , angiotensin ii , neovascularization , endocrinology , renin–angiotensin system , cancer , cancer research , blood pressure
BACKGROUND Prostate cancer is the most frequently diagnosed malignancy and the second‐leading cause of cancer death in men. The purpose of this study was to determine the anti‐proliferative and anti‐angiogenic efficacy of angiotensin‐(1‐7) [Ang‐(1‐7)], an endogenous peptide hormone, in human prostate cancer xenografts. METHODS Human LNCaP prostate cancer cells were injected into the flank of athymic mice and tumors were treated with Ang‐(1‐7) for 54 days. Tumor growth and angiogenesis were determined by immunohistochemistry and western blot hybridization. RESULTS Ang‐(1‐7) markedly reduced the volume and wet weight of LNCaP xenograft tumors. Histological analysis of tumor sections from saline‐treated mice showed increased Ki67 immunoreactivity and enhanced phosphorylation of the MAP kinases ERK1/2 compared to tumors from Ang‐(1‐7)‐treated mice, suggesting that the heptapeptide reduces cell proliferation. Intratumoral vessel density was decreased in Ang‐(1‐7)‐treated mice with an associated reduction in vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), suggesting that the heptapeptide attenuates vascularization by reducing angiogenic factors. Ang‐(1‐7) administration markedly increased the soluble fraction of VEGF receptor 1 (sFlt‐1), with a concomitant reduction in VEGF receptors 1 and 2. sFlt‐1 serves as a decoy receptor that traps VEGF and PlGF, making the ligands unavailable to membrane‐bound VEGF receptors and preventing activation of pro‐angiogenic signaling. CONCLUSIONS The decrease in PlGF and VEGF coupled with the increase in sFlt‐1 suggests that Ang‐(1‐7) may serve as a novel anti‐angiogenic therapy for prostate cancer. Further, the pleiotropic mechanisms of action by Ang‐(1‐7) may limit angiogenic resistance that occurs with VEGF inhibitors or receptor blockers. Prostate 73: 60–70, 2013. © 2012 Wiley Periodicals, Inc.