IL-33 released during liver resection facilitates intrahepatic cholangiocarcinoma growth via cytokine secretion in cancer-associated fibroblasts.

BACKGROUND: We previously reported that IL-33 released during hepatectomy contributes to cytokine-facilitated iCCA tumor growth. However, the underlying mechanisms of the tumor microenvironment remain unexplored. In this study, we aimed to elucidate the impact of IL-33 on cancer-associated fibroblasts (CAFs). METHODS: The abundance of IL-33-positive cells and alpha-SMA-positive fibroblasts (myoCAFs) was evaluated using resected specimens. Next-generation sequencing (NGS) was performed for comprehensive expression analysis. The effects of IL-33 stimulation on CAFs were investigated in vitro and in vivo using human and murine iCCA cell lines, as well as fibroblasts extracted from resected specimens. RESULTS: IL-33-positive cells and myoCAFs were significant risk factors for intrahepatic recurrence. NGS analysis revealed significant upregulation of various cytokines in cases with high number of IL-33-positive cells. The conditioned medium obtained from fibroblasts stimulated with IL-33 enhanced the proliferation and migration of iCCA cell lines. Among the cytokines that were increased by IL-33 stimulation in vitro, IL-6 was suspected to be the dominant. In a murine syngraft model, hepatectomy led to an increased subcutaneous tumor volume by releasing IL-33, whereas IL-6 blockade suppressed this growth. CONCLUSIONS: This study indicated that IL-33 facilitates iCCA growth through fibroblast activation and is associated with intrahepatic recurrence.