Abstract A29: Effects of obesity on regulation of macrophage population in the prostate tumor microenvironment

Abstract

Abstract Background: Obesity is associated with a greater risk of prostate cancer mortality, but the mechanisms driving this progression are still unclear. A high concentration of macrophages within the tumor microenvironment, especially tumor-associated macrophages (TAMs), has been linked to progression and metastasis in numerous cancer types, including prostate. Obesity increases circulating levels of monocyte chemotactic protein-1 (MCP-1), a chemokine involved in monocyte migration. In addition, prostaglandin E2 (PGE2), a molecule closely associated with obesity, appears to be involved in macrophage polarization. Our preliminary in vitro data suggest that obese conditions promote both macrophage recruitment and TAM polarization. Hypothesis: Based upon these preliminary results, we hypothesize that obesity-induced prostate cancer progression is due, in part, to increased TAM concentrations in the prostate tumor micro-environment, promoting pro-metastatic signaling. Methods: In order to mimic the prostate tumor microenvironment, an in vitro model composed of adipose stromal cells, macrophages, prostate cancer epithelial cells and sera from obese and non-obese men was used to assess the impact of obesity on the paracrine signaling network. Matrigel invasion chambers were used to assess macrophage recruitment. qPCR was used to measure mRNA levels of proteins associated with a TAM phenotype as well as mRNA levels of MCP-1 and cyclooxygenase-2 (COX-2), an enzyme involved in PGE2 production. Results: Obese conditions resulted in increased macrophage recruitment and increased mRNA levels of TAM markers in macrophages. Furthermore, MCP-1 mRNA levels in adipose stromal cells and prostate cancer cells were higher under obese conditions compared to non-obese conditions. Similarly, obese conditions increased COX-2 mRNA levels in prostate cancer cells. Conclusions: Data from our in vitro study suggest that obesity may promote macrophage infiltration into the prostate tumor microenvironment and play a role in macrophage polarization towards a tumor-associated phenotype. This study will potentially serve to determine the value of macrophage and TAM concentration as biomarkers in this patient population, and lay the foundation for future studies investigating whether this phenomenon might be an effective therapeutic target. Citation Format: Gloria C. Galvan, Shruti Apte, Linda A. deGraffenried. Effects of obesity on regulation of macrophage population in the prostate tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A29.