Abstract 1103: Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis

Abstract

Abstract Liver metastases develop in more than half of patients with colorectal cancer (CRC) and indicate a poor prognosis. In this study, we aim to investigate CRC-derived small extracellular vesicles (CRC-sEVs) participating in liver-specific metastasis. Fluorescence-labeled CRC-sEVs were found to accumulate in macrophages in mouse liver and prime macrophage polarization toward an interleukin-6 (IL-6)-secreting pro-inflammatory phenotype (macrophage expresses different programs in response to different microenvironmental signals called macrophage polarization). By analyzing miRNA expression profiles of the CRC-sEVs and their parental cells (SW480 and SW620), we identified miR-21-5p (miR-21) as the top ranked miRNA that was highly upregulated both in the sEVs and their parental CRC cells. The majority of macrophage-secreted inflammatory signaling pathways are activated by Toll-like receptor (TLR). Macrophages treated with miR-21 analogs exhibited enhanced expression of pro-inflammatory cytokines such as IL-6 and TNF-α. Silencing either miR-21 in CRC-sEVs, or the Toll-like receptor 7 (TLR7) in macrophages which miR-21 binds to, abolished the effect of CRC-sEVs in inducing pro-inflammatory macrophage polarization. Upon intravenous injection, CRC-sEVs promoted miR-21 expression and macrophage infiltration in the mouse liver, followed by the up-regulation of inflammatory genes. Accordingly, the multiplicity of liver metastases was increased upon transplantation of CRC cells in mice treated with CRC-sEVs. Furthermore, miR-21 expression in plasma-derived sEVs positively correlated with tumor stage and liver metastasis in CRC patients. Finally, co-expression of the miR-21 and IL-6 macrophages markers was observed in liver metastatic tissues from CRC patients. Together, our data point to a pivotal role of CRC-sEVs in inducing an inflammatory pre-metastatic niche through the miR-21-TLR7-IL6 axis. Moreover, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis. Citation Format: Yingkuan Shao, Ting Chen, Xi Zheng, Shu Zheng. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1103.