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

By J. L. Hu, Wen Wang, X. Lan, Zhicheng Zeng, Yunshi Liang, Yongrong Yan, F. Song, Fan Wang, Xin-Hong Zhu, W. Liao and 3 more. Molecular Cancer, 2019

678 citations recorded by the source corpus.

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. 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. CAFs 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. CAFs 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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8549ccee85246ef29f5bc88d449d4e0190972d75

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Citations in the corpus

• Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities (2022, background): “Highly expressed miR-92a-3p reduces the ubiquitin-mediated degradation of β-catenin by directly inhibiting FBXW7 and MOAP1 and promoting the progression of colorectal cancer (CRC).(55) MiR-182-5p directly inhibits the expression of FOXO3a, preventing its binding to β-catenin, enhancing the interacti”
• Wnt signaling in colorectal cancer: pathogenic role and therapeutic target (2022, background): “In terms of mechanism, the increased expression of miR-92a-3p activates the Wnt/β-catenin pathway, inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, and promotes the stem cell, EMT, and metastasis of colorectal cancer cells [128].”
• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “CAFs is crucial in cancer progression by contributing to the promotion of the EMT, cancer metastasis and chemotherapy resistance [158, 159].”