Abstract A37: The role of IL-6 in the interaction between fibroblasts and tumor cells in esophageal adenocarcinoma
Authors: Lin Eric W. , Karakasheva Tatiana A. , Derks Sarah , Wong Kwok K. , Bass Adam J. , Rustgi Anil K. 
Published: October 2016

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.