Snail Overexpression Alters the microRNA Content of Extracellular Vesicles Released from HT29 Colorectal Cancer Cells and Activates Pro-Inflammatory State In Vivo

SIMPLE SUMMARY: Knowledge of the factors that help migration of carcinoma cells is important for prevention of metastasis. Cancer cells release small particles, extracellular vesicles (EVs) that contain such factors. The aim of this study was to assess if the content of EVs changes through different stages of colorectal cancer (CRC) and evaluate how this process affects cancer progression in vivo in mouse CRC model. We found that EVs released from cells that have migratory properties contain different factors then EVs released from original tumor cells. We also show here that EVs can be incorporated into other cells that facilitate metastasis and change their properties depending on the EVs content. The content of cell-released EVs may also serve as a biomarker that denotes the stage of CRC and may be a target to prevent cancer progression. ABSTRACT: During metastasis, cancer cells undergo phenotype changes in the epithelial-mesenchymal transition (EMT) process. Extracellular vesicles (EVs) released by cancer cells are the mediators of intercellular communication and play a role in metastatic process. Knowledge of factors that influence the modifications of the pre-metastatic niche for the migrating carcinoma cells is important for prevention of metastasis. We focus here on how cancer progression is affected by EVs released from either epithelial-like HT29-cells or from cells that are in early EMT stage triggered by Snail transcription factor (HT29-Snail). We found that EVs released from HT29-Snail, as compared to HT29-pcDNA cells, have a different microRNA profile. We observed the presence of interstitial pneumonias in the lungs of mice injected with HT29-Snail cells and the percent of mice with lung inflammation was higher after injection of HT29-Snail-EVs. Incorporation of EVs released from HT29-pcDNA, but not released from HT29-Snail, leads to the increased secretion of IL-8 from macrophages. We conclude that Snail modifications of CRC cells towards more invasive phenotype also alter the microRNA cargo of released EVs. The content of cell-released EVs may serve as a biomarker that denotes the stage of CRC and EVs-specific microRNAs may be a target to prevent cancer progression.