Abstract P5-03-10: IL-6 and CCL5 secretion by adipose-derived stem cells and the breast tumor microenvironment

Abstract

Abstract Introduction: Obesity is a key factor in promoting aggressive breast cancers in women. In previous studies, we found increased production of IL-6 and CCL5, common pro-inflammatory cytokines, in co-cultures of adipose stem cells and triple negative breast tumor cells. When we probed The Cancer Genome Atlas (TCGA) for triple negative breast cancer, we discovered that CCL5 overexpression was associated with improved survival. This finding contradicts the majority of in vitro studies regarding the role of CCL5 in the breast tumor microenvironment; the literature suggests that CCL5 promotes tumor metastatic ability. Furthermore, TCGA data did not indicate a significant correlation between IL-6 production and survival outcomes. It remains unclear whether CCL5 and IL-6 are produced by adipose stromal cells or cancer cells within the tumor microenvironment. We predict that the primary source of CCL5 and IL-6 is from adipose stromal cells. However, the production of these cytokines may be altered when exposed to tumor-secreted factors. Methods: Adipose-derived stem cells (ASC) and preadipocytes differentiated from ASCs (Pread(A)) were treated with the conditioned media of triple negative breast tumor cells (MDA-MB-231) and luminal A breast tumor cells (MCF-7). In addition, MDA-MB-231 and MCF-7 cells were treated with the conditioned media of each adipose stromal cell type. After 72 hours of treatment, the media harvested from each cell type was analyzed for secreted IL-6 and CCL5 proteins. Results: IL-6 and CCL5 levels in the conditioned media of ASCs treated with MDA-MB-231 or MCF-7 cells were significantly lower (p<0.05) when compared to the media of ASCs alone. The reverse occurred when tumor cells were provided conditioned media from adipose progenitor cells. When both breast tumor cell lines were exposed to conditioned media from ASCs and Pread(A), the secretion of IL-6 and CCL5 increased significantly (p<0.05). The conditioned media of Pread(A) cells treated with breast tumor cells were lower than untreated cells, however, this decrease in cytokine production was not significant. Conclusions: This study suggests that IL-6 and CCL5 secretion by adipocytes is modified by the presence of breast tumor cells. The significant decrease in IL-6 and CCL5 secretion from both adipose-derived stem cells and preadipocytes in the presence of tumor may suggest an attempt by the tumor to inhibit an inflammatory response by adipose stromal cells while increasing its own IL-6 and CCL5 production. Although the human genome data indicates that CCL5 and IL-6 provide a survival benefit in vivo, laboratory in vitro studies thus far have failed to mimic the observed clinical responses. Further studies will investigate the clinical relevance of CCL5 and IL-6 receptors in breast cancer. (Supported by NIH P20GM103434 and NIGMS U54GM104942) Citation Format: Vona-Davis L, Lundstrom E, Berrebi D, Werwie N, Yadav A. IL-6 and CCL5 secretion by adipose-derived stem cells and the breast tumor microenvironment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-03-10.