Abstract
BackgroundCancer 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.MethodsCAFs 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.ResultsCAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.ConclusionsCAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
Highlights
Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer-related deaths worldwide [1]
MiR-92a-3p expression is significantly increased in colorectal cancer (CRC) tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients
Cancer associated fibroblasts (CAFs) were positive for alpha-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), fibroblast specific protein 1 (FSP-1) and mesenchymal marker vimentin, while normal fibroblasts (NFs) weakly expressed these proteins (Additional file 1: Figure S1B-D)
Summary
Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer-related deaths worldwide [1]. The mechanisms of CRC metastasis and chemotherapy resistance remain unclear. Accumulating evidence have shown that the cellular interaction between cancer cells and surrounding stroma cells in tumor microenvironment (TME) play important roles in regulating cancer progression and therapy response [3,4,5]. CAFs are vital constituents of the TME that interact with cancer cells to promote tumorigenesis and progression. The mechanisms of CAFs promoting cancer metastasis and chemotherapy resistance, as well as the communication between CAFs and cancer cells remain to be investigated. Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. The CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized
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