Abstract 2383: IL-6 and RANTES mediate the cross-talk between tumor cells and CAFs in the esophageal tumor microenvironment

Desmoplasia, or deposition of connective tissue proper in the stroma, is a key characteristic of esophageal squamous cell carcinoma (ESCC). The cellular component of connective tissue proper is comprised of fibroblasts, and cancer-associated fibroblasts (CAFs) are widely recognized as a major constituent of the tumor microenvironment (TME). The purpose of this study was to identify tumor-promoting factors that are secreted as a result of the crosstalk between CAFs and tumor cells in ESCC. We have performed a comprehensive cytokine array and found that IL-6 and RANTES (also known as CCL5) are significantly overexpressed in conditioned media from co-culture of esophageal CAFs and ESCC cells, compared to mono-culture. Both proteins are known to play important roles in the development of multiple types of cancer, mostly via activation of the STAT3 signaling pathway. We have demonstrated that co-culture with fibroblasts prompts the ESCC cells to acquire a more mesenchymal phenotype and express potent mediators of cell migration and invasion, such as matricellular proteins (periostin, fibrillin, osteonectin) and hepatocellular growth factor (HGF). Furthermore, knockdown of IL-6 suppresses invasiveness and proliferation of human ESCC cells in our 3D organotypic culture model. We have also performed staining of tissue samples from ESCC patients and found that, compared to normal esophagus, expression of IL-6 and RANTES is enhanced in ESCC in both epithelial cells and fibroblasts. In summary, our findings indicate that IL-6 and RANTES are responsible for migration and invasion of ESCC cells promoted by CAFs in the tumor microenvironment. This is the first report of such a dual induction of these specific cytokines in ESCC, and it provides a rationale for dual inhibition of IL-6 and RANTES as novel therapy for ESCC, and possibly other types of cancer. Supported by NCI P01 CA098101. Citation Format: Tatiana A. Karakasheva, Monica Soni, Todd Waldron, Anil K. Rustgi. IL-6 and RANTES mediate the cross-talk between tumor cells and CAFs in the esophageal tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2383. doi:10.1158/1538-7445.AM2015-2383