Abstract 429: Novel role of CXCL12/CXCR4 signaling axis in obesity-induced prostate cancer progression in HiMyc mice

Abstract

Abstract Obesity has been shown to increase prostate cancer (PCa) progression and disease severity in men. In previous studies, we showed that diet-induced obesity (DIO, 60 kcal% fat) increased the incidence and severity of invasive adenocarcinomas in HiMyc transgenic mice compared to mice on a control diet (10 kcal% fat) whereas calorie restriction (30% CR) completely prevented the formation of adenocarcinomas. Increased tumor progression was associated with changes in expression of a large number of cytokines, chemokines and growth factors suggesting that altered growth factor and inflammatory signaling pathways in the tumor microenvironment may be key targets for preventing and controlling PCa progression and especially obesity-related PCa progression. Therefore, in this study we investigated the role of white adipose tissue (WAT)-derived factors on obesity-driven PCa progression in HiMyc mice. We first isolated RNA from the stromal vascular fraction (SVF) of the periprostatic WAT from HiMyc mice maintained on DIO and control diet. qPCR analyses showed a dramatic increase in expression of various chemokines, cytokines, growth and angiogenesis factors in the SVF of obese HiMyc mice. Among them, both CXCL12 and its receptors CXCR4 and CXCR7, were significantly upregulated in SVF from obese HiMyc mice. Recently, we developed a PCa cell line from the ventral prostate of HiMyc mice (HMVP2 cells) and a normal cell line from FVB/N mice (NMVP cells). Two additional cell lines (HMVP2A1 and HMVP2A2) were isolated from the original HMVP2 cells after subsequent tumor formation in FVB/N mice and growth in culture. HMVP2 and the derivative cell lines have characteristics of cancer stem cells and produce tumors in syngeneic mice. Western blot analyses showed expression of both CXCR4 and CXCR7 in the following order HMVP2A2 >HMVP2A1> HMVP2>NMVP cells, which followed their ability to produce tumors in vivo. Furthermore, CXCL12 treatment stimulated migration and invasion of HMVP2 cells (but not NMVP cells), which was inhibited by the CXCR4 antagonist, AMD3100. CXCL12 treatment also led to rapid activation of Akt, Stat3 and NFκB signaling in HMVP2 but not in NMVP cells. These data suggest that CXCL12 has differential effects on PCa cells from HiMyc mice compared to normal prostate cells that may play a role in driving tumor progression. In addition, these data suggest that targeting the CXCL12/CXCR4/CXCR7 axis could lead to novel approaches for offset the effects of obesity on PCa progression, thereby reducing PCa mortality. Citation Format: Achinto Saha, Jorge Blando, John DiGiovanni. Novel role of CXCL12/CXCR4 signaling axis in obesity-induced prostate cancer progression in HiMyc mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 429. doi:10.1158/1538-7445.AM2015-429