CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer

作者：Jinwei Hu, Wei Wang, Xiao-Liang Lan, Zhao‐Chong Zeng, Yingke Liang, Yuhui Yan, Fuyao Song, Fangfang Wang, Xiaoxia Zhu, Wenting Liao, Wenjie Liao, Yanqing Ding, Liang Li · 发表于：Molecular Cancer · 年份：2019 · DOI：10.1186/s12943-019-1019-x · 被引用次数：827 · 研究领域：Extracellular vesicles in disease、Cancer Cells and Metastasis、MicroRNA in disease regulation

BACKGROUND: Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. METHODS: CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. RESULTS: CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resi...