Abstract 1966: Obesity and prostate cancer progression: Role of the chemokine CXCL12

Abstract

Abstract Obesity is a significant risk factor for several cancers in both men and women. A number of studies have shown that obesity is associated with increased prostate cancer (PCa) progression and higher mortality. However, the mechanism(s) for obesity-driven PCa remain unclear. In earlier studies, we showed that obesity enhances PCa progression in the HiMyc mouse model by changing the surrounding tumor microenvironment, especially the white adipose tissue (WAT). WAT consists of many cells including inflammatory cells, mature adipocytes and adipose stromal cells (ASCs). Here, we further investigated the role of ASCs and ASC derived CXCL12 in obesity-driven PCa progression. In HMVP2 cells, a PCa cell line derived from HiMyc mice expressing high levels of CXCR4, we observed activation of MAPKs (JNK and ERK), AKT, STAT3 and NFkB following treatment with CXCL12. These CXCL12-induced signaling pathways were inhibited by treating with AMD3100, a CXCR4 antagonist, and also by CXCR4 knock-down. To confirm this in vivo, we compared PCa tumor growth in lean and obese mice using the HMVP2 allograft model. Our data demonstrates that obesity promotes EMT in tumor cells and increases invasion of surrounding WAT into the tumor stoma. Treatment of mice with AMD3100 significantly inhibited the growth of HMVP2 tumors and suppressed EMT in both the obese and control diet groups. Furthermore, D-CAN, a hunter-killer peptide developed for targeting ASCs, also suppressed obesity-induced EMT and tumor growth in HMVP2 tumor allografts. Lastly, AMD3100 in combination with D-CAN, showed a significant reduction in PCa growth in obese mice compared to either agent used alone. These results provide evidence that ASCs activate the CXCL12/CXCR4 signaling as well as other pathways playing an important role in obesity-driven PCa progression. Our data suggests this pathway as a novel therapeutic target for inhibiting obesity-driven PCa growth and progression. Research supported by NCI Grant CA196259. Citation Format: Songyeon Ahn, Achinto Saha, Mikhail G. Kolonin, John DiGiovanni. Obesity and prostate cancer progression: Role of the chemokine CXCL12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1966.