Cytokines Released from Activated Human Macrophages Induce Epithelial Mesenchymal Transition Markers of Cholangiocarcinoma Cells

Stromal-epithelial interactions are important for carcinogenesis. Once cancerous lesions develop, a chronically inflamed tumor microenvironment promotes migration and invasion of tumor cells. Multiple immune cell populations are involved in inflammatory processes, including tumor-associated macrophages (TAMs) which have been proposed as major contributors to tumor progression. The epithelial-mesenchymal transition (EMT) is a process in which epithelial cells trans-differentiate and acquire an invasive mesenchymal phenotype. As EMT represents a crucial step in disease progression, it is important to investigate the mechanisms regulating this step. We aimed to identify the profiles of cytokines produced by activated human macrophages and to demonstrate effects on the expression of EMT-related genes in human cholangiocarcinoma (CCA) cell lines. Our results showed that LPS-activated macrophages produced and secreted IL4, IL6, IL10, TNF-alpha and TGF-beta 1. After addition of macrophage conditioning media to CCA cells, expression of epithelial markers E-cadherin and CK-19 was significantly reduced, whereas the expression of mesenchymal markers, S100A4 and MMP9 was strongly induced. Taken together, various cytokines secreted by activated macrophages could induce EMT by altering the expression of EMT-related genes in CCA.