Abstract 1299: Angiotensin-(1-7) inhibits angiogenesis in human prostate cancer xenografts through an increase in soluble vascular endothelial growth factor receptor 1 (sFLT1)
Authors: Krishnan Bhavani , Gallagher Patricia E. , Tallant E Ann 
Published: February 2011

Abstract
Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. We showed that angiotensin-(1-7) [Ang-(1-7)], a seven amino acid peptide hormone of the renin-angiotensin system, significantly inhibited the proliferation of human lung cancer cells and attenuated the growth of non-small cell adenocarcinoma tumors in a xenograft model, with an associated reduction in angiogenesis. Since previous epidemiological studies suggest that treatment with anti-hypertensive drugs which increase Ang-(1-7) reduces the risk of sex-specific cancers, we investigated the effects of the heptapeptide on prostate cancer. Ang-(1-7) significantly reduced the growth of both androgen-responsive LNCaP human prostate cancer cells and PC3 cells derived from a bone metastasis of a patient with prostate cancer. Athymic mice with xenograft LNCaP human prostate tumors were treated with Ang-(1-7) for 54 days. Treatment with the heptapeptide resulted in an 84.5% reduction in tumor volume and a 72% decrease in tumor weight. The reduction in tumor size was associated with a 78% decrease in Ki67 immunoreactivity, suggesting that Ang-(1-7) inhibits tumor cell proliferation. Treatment with the heptapeptide also caused a 50% decrease in the density of tumor vessels, identified by morphology using an antibody to CD34 to label endothelial cells, suggesting that Ang-(1-7) reduces angiogenesis. The reduction in angiogenesis by heptapeptide administration was associated with a decrease in the mRNA and protein of vascular endothelial growth factor (VEGF) (a 48% reduction in protein and an 82% reduction in mRNA) and placental growth factor (PlGF) (a 72% reduction in both protein and mRNA), key factors involved in angiogenesis. Incubation of LnCaP cells with 100 nM Ang-(1-7) for 24 h also caused a significant reduction in the secretion of both VEGF (64%) and PlGF (71%). The decrease in PlGF and VEGF correlated with a 12-fold increase in the soluble fraction of VEGF receptor 1 (sFLT1) [from 0.12 ± 0.06 relative density units in tumors from saline-treated mice compared to 1.41 ± 0.30 relative density units in tumors from Ang-(1-7)-treated mice, n = 5, p &lt; 0.001]. sFLT1 is a decoy receptor that traps PlGF and VEGF, making the ligands unavailable to membrane-associated VEGF receptors and blocking activation of key angiogenic signaling pathway. While anti-angiogenic therapies targeting VEGF revolutionized cancer treatment, tumors develop resistance to these agents and patients have an increased risk of developing metastases, which may result from production of alternate pro-angiogenic factors, such as PlGF. Since treatment with Ang-(1-7) reduces both VEGF and PlGF and concomitantly increases sFLT1 to attenuate angiogenic signaling, the heptapeptide may represent a novel anti-angiogenic therapeutic in the treatment of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1299.