Abstract 502: Circulating exosomal miR-203 is associated with metastasis via inducing tumor-associated macrophages in colorectal cancer

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Abstract Distant metastasis is the leading cause of mortality in patients with malignant tumor including colorectal cancer (CRC). A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis by communicating with host cells. However, little is known about the communicating mechanism is known. Understanding this mechanism should uncover a new field of cancer therapy through the targeting of the interaction between tumor and host. In this study, we focused on circulating microRNAs (miRs) as the communication tool between host and tumor cells that were mainly carried by exosomes in circulation. As a result of gene expression microarray and gene set enrichment analysis, we identified miR-203 as a putative signaling molecule between tumors and monocytes in metastatic CRC patients. The level of miR-203 expression was significantly upregulated in a TNM stage-dependent manner. High exosomal miR-203 expression in serum was significantly associated with poor DFS and OS (P < 0.01), and was an independent poor prognostic factor. Additionally, high exosomal miR-203 was associated with distant metastasis (P < 0.01). We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 promoted the expression of M2 markers such as CD163 and STAT3 in vitro. It suggested that serum exosomal miR-203 released from CRC cells promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs) which facilitated premetastatic niche and distant metastasis. Co-injection of miR-203-transfected CRC cells and monocyte increased a ratio of liver metastasis in vivo compared with only control CRC cells or only miR-203-transfected CRC cells injection. On the other hand, overexpression of miR-203 did not increase the proliferation, invasion and migration capacity of CRC cells. This results indicated that serum exosomal miR-203 might create a premetastatic niche whereas did not affect to malignant phenotype of CRC cells. Our study indicated that serum exosomal miR-203 expression could be a novel and feasible biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Citation Format: Dai Shimizu, Takaaki Masuda, Yuki Takano, Hisae Imamura, Rui Yamaguchi, Kuniaki Sato, Taro Tobo, Hidenari Hirata, Yosuke Kuroda, Sho Nambara, Naoki Hayashi, Tomohiro Iguchi, Shuhei Ito, Hidetoshi Eguchi, Takahiro Ochiya, Katsuhiko Yanaga, Satoru Miyano, Koshi Mimori. Circulating exosomal miR-203 is associated with metastasis via inducing tumor-associated macrophages in colorectal cancer [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 502.