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

Abstract

Stromal-epithelial interactions are important for carcinogenesis. Once cancerous lesions develop, a chronicallyinflamed tumor microenvironment promotes migration and invasion of tumor cells. Multiple immune cellpopulations are involved in inflammatory processes, including tumor-associated macrophages (TAMs) whichhave 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. AsEMT represents a crucial step in disease progression, it is important to investigate the mechanisms regulatingthis step. We aimed to identify the profiles of cytokines produced by activated human macrophages and todemonstrate effects on the expression of EMT-related genes in human cholangiocarcinoma (CCA) cell lines. Ourresults showed that LPS-activated macrophages produced and secreted IL4, IL6, IL10, TNF-α and TGF-β1.After addition of macrophage conditioning media to CCA cells, expression of epithelial markers E-cadherinand CK-19 was significantly reduced, whereas the expression of mesenchymal markers, S100A4 and MMP9was strongly induced. Taken together, various cytokines secreted by activated macrophages could induce EMTby altering the expression of EMT-related genes in CCA.