Abstract A37: The role of IL-6 in the interaction between fibroblasts and tumor cells in esophageal adenocarcinoma

Often described as wounds that do not heal, cancer cells depend on interactions with the surrounding stroma to develop and progress. Among the various stromal components, cancer-associated fibroblasts (CAFs) play a critical role in promoting tumor growth and invasion, leading to treatment resistance and poor survival in a number of cancers, including esophageal adenocarcinoma. Mechanistically, CAFs communicate with tumor cells in large part via secreted signaling factors. One such factor, interleukin-6 (IL-6), has been shown to be secreted by CAFs to promote angiogenesis, epithelial-to-mesenchymal transition (EMT), tumor cell stemness, and treatment resistance in adenocarcinomas of the colon, pancreas, stomach, and breast. In EAC, the upregulation of IL-6 signaling among tumor cells, particularly as a result of exposure to reflux, is well characterized. However, the role of IL-6 as a potential mediator of the CAF-tumor cell interaction in EAC remains poorly understood. To confirm that IL-6 is indeed involved in this interaction, we used ELISA to study the dynamics of IL-6 secretion by activated fibroblasts (FEF3303, FEF3 and PDF.G.P) and EAC cells (OE-19 and OE-33) in the setting of mono- and co-culture. We found that the interaction of CAFs and EAC cells in co-culture dramatically increased IL-6 levels compared to either EAC cells or fibroblasts alone. Next, we considered the relevance of these findings to human disease by examining human EAC biopsy specimens for patterns of IL-6 expression via immunohistochemical staining. IL-6 was strongly expressed in the tumor-associated stroma of 10/10 EAC biopsy specimens, with 5/10 showing tumor expression as well, which in several cases was localized to the invasive edge near the tumor-stromal interface. In addition, to assess for IL-6 signaling, we stained the sections for downstream mediators of IL-6 signaling, namely STAT3 and ERK1/2. We found nuclear localization of STAT3 and ERK in 10/10 and 7/10 samples, respectively, indicating activation of these pathways. In summary, our findings indicate that IL-6 is involved in the communication between CAFs and tumor cells in EAC. Furthermore, we have reason to believe, especially in cases where both tumor cells and stroma have strong IL-6 expression, that IL-6 may be a mediator of a bidirectional “crosstalk” between these two cell types. Additional investigation, for instance with the use of a 3-D organotypic model of EAC, will help to further characterize the functional role of IL-6 in this context. This is the first report describing a potential role for IL-6 in mediating crosstalk between CAFs and tumor cells in EAC. Citation Format: Eric W. Lin, Tatiana A. Karakasheva, Sarah Derks, Kwok K. Wong, Adam J. Bass, Anil K. Rustgi. The role of IL-6 in the interaction between fibroblasts and tumor cells in esophageal adenocarcinoma. [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 A37.