Tumor‐secreted extracellular vesicles promote the activation of cancer‐associated fibroblasts via the transfer of microRNA‐125b

Abstract

Tumour cells release large quantities of extracellular vesicles (EVs) to mediate their interactions with other cells in the tumour microenvironment. To identify host cells that naturally take up EVs from tumour cells, we created breast cancer cell lines secreting fluorescent EVs. These fluorescent EVs are taken up most robustly by fibroblasts within the tumour microenvironment. RNA sequencing indicated that miR-125b is one of the most abundant microRNAs secreted by mouse triple-negative breast cancer 4T1 and 4TO7 cells. Treatment with 4T1 EVs leads to an increase in fibroblast activation in isogenic 4TO7 tumours, which is reversed by blocking miR-125b in 4T1 EVs; hence, miR-125b delivery by EVs is responsible for fibroblast activation in mouse tumour models. miR-125b is also secreted by human breast cancer cells and the uptake of EVs from these cells significantly increases cellular levels of miR-125b and expression of multiple cancer-associated fibroblast markers in resident fibroblasts. Overexpression of miR-125b in both mouse and human fibroblasts leads to an activated phenotype similar to the knockdown of established miR-125b target mRNAs. These data indicate that miR-125b is transferred through EVs from breast cancer cells to normal fibroblasts within the tumour microenvironment and contributes to their development into cancer-associated fibroblasts.

Breast Milk, a Source of Beneficial Microbes and Associated Benefits for Infant Health

“…MicroRNAs or miRNAs are small noncoding RNA molecules that play an important role in the regulation of gene expression at the post-transcriptional level [113]. MicroRNAs have been identified across plants, animals, and viruses and within a number of human body fluids such as blood, breast milk, urine, and saliva [114][115][116][117][118][119][120][121]. These molecules can be secreted into extracellular fluid where they can be packaged into exosomes, which are membrane vesicles which contain various microRNAs [122][123][124].…”

The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis

“…MiRNAs are among the most abundant cargo found in EVs; as such, it is unsurprising that EV-mediated miRNA transfer from cancer to stromal cells plays an important role in promoting CAF differentiation. To date, at least two dozen miRNAs have been found to be responsible for promoting EV-mediated CAF differentiation in a variety of cancer types [11,95,[98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]. Uptake of miRNA-containing EVs into recipient cells results in altered expression of key signaling pathways, many of which have a known oncogenic or tumor-suppressive role, which leads to the adoption of a CAF phenotype.…”

Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer

“…In fact, the effects induced by EVs are related to modulation of the immune response. Furthermore, it has been demonstrated that EVs of tumor cells are capable of promoting immune escape by determining regulatory T cell expansion [ 159 ] and by shedding FAS ligand (FASL), as well as by inducing CD8 + T cell apoptosis and increasing expression of the MMP9 gene in melanoma cells [ 79 , 160 ].…”