Abstract 5421: Stage specific inhibitory effect and associated mechanisms of insositol hexaphosphate on tumor progression and angiogenesis in TRAMP model

Abstract

Prostate cancer (PCa) is the leading cause of cancer-related deaths in elderly men in US; ACS’ statistical estimates for 2011 report ∼240,890 new PCa cases and 33,720 associated deaths. In recent years, transgenic adenocarcinoma of the mouse prostate (TRAMP) has been the most frequently employed PCa model to evaluate chemopreventive efficacy of various agents. This model closely mimics human form of the disease, wherein prostate carcinogenesis progresses in a step-wise manner with the age of the mouse. The well defined stages of prostate tumor growth, progression and angiogenesis in TRAMP model provide unique opportunity to assess ‘stage specific’ preventive efficacy of an agent. Accordingly, employing TRAMP model, here we assessed stage-specific efficacy of inositol hexaphosphate (IP6) feeding on PCa initiation and growth, progression and angiogenesis, and elucidated the molecular events involved in IP6 effects during these stages. Different groups of male TRAMP mice starting at 4, 12, 20 and 30 weeks of age were fed with regular drinking water or 2% IP6 in regular drinking water for 8-10 weeks. At the end of the study, histopathological analysis of prostate showed that all the mice fed with IP6 at different time-points display less severe prostatic lesions compared to non-IP6 fed positive control mice. During early stages of prostate tumor development, IP6 mediated its chemopreventive effect mostly via anti-proliferative and pro-apoptotic mechanisms. Feeding of IP6 to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via anti-proliferative effect and inhibition of angiogenesis as evidenced by decreased expression of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD-31), vascular endothelial growth factor (VEGF) hypoxia-inducible factor-1a (HIF-1a) and inducible nitric oxide synthase (iNOS). These effects of IP6 also correlated with an alteration of epithelial-mesenchymal transition (EMT) as was evidenced by a decreased expression of mesenchymal markers Snail-1 in the prostatic tissue and retention of epithelial characteristics determined by localization of E-cadherin. Together, the findings in the present study are both novel and highly significant in establishing the dual efficacy of IP6, where it inhibits initiation and progression of primary prostatic tumor and also exerts protective efficacy against angiogenesis. These effects of IP6 should have potential implications to control PCa growth and improve the morbidity and survival time in PCa patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5421. doi:1538-7445.AM2012-5421