Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression

Abstract

The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer‐associated fibroblasts, play a pivotal role. TP53‐deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53‐deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell‐derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53‐WT colon cancer, HCT116; TP53‐mutant colon cancer, HT29; and fibroblasts, CCD‐18Co and WI‐38) and an immune‐deficient nude mouse xenograft model. HCT116 (HCT116sh p53) cells deficient in TP53 accelerated cocultured fibroblast proliferation compared to TP53‐WT HCT116 (HCT116sh control) cells in vitro. Exosomes from HCT116sh p53 cells suppressed TP53 expression of fibroblasts and promoted their proliferation. Xenografts of HCT116sh p53 cells grew significantly faster than those of HCT116sh control cells in the presence of co‐injected fibroblasts, but this difference was diminished by CDE inhibition. Microarray analysis identified upregulation of several microRNAs (miR‐1249‐5p, miR‐6737‐5p, and miR‐6819‐5p) in TP53‐deficient CDEs, which were functionally proven to suppress TP53 expression in fibroblasts. Exosomes derived from TP53‐mutant HT29 cells also suppressed TP53 expression in fibroblasts and accelerated their growth. The proliferative effect of HT29 on cocultured fibroblasts was diminished by inhibition of these miRNAs in fibroblasts. Our results suggest that CDEs play a pivotal role in tumor progression by fibroblast modification. Cancer cell‐derived exosomes might, therefore, represent a novel therapeutic target in colon cancer.

Exosomal miRNAs in tumor microenvironment

“…Exosomal miRNAs have found similar effects in colorectal cancer (CRC). Exosomal miR-2149-5p, miR-6737-5p, and miR-6819-5p can inhibit the expression of TP53 in fibroblasts to promote tumor proliferation [108].…”

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression

“…Exosomes are nano-sized microvesicles composed of lipid bilayer and contain various bioactive molecules, including miRNA, long non-coding RNA, circular RNAs, which are considered as mediators for intercellular communication [7,8]. Recently, exosomal microRNAs (exomiRs) have drawn much attention because numerous studies have demonstrated that exomiRs can influence many hallmarks of cancer, such as cancer development, progression, and metastasis [9][10][11][12], and more evidences have suggested that exomiRs are highly suitable candidates for use as biomarkers in an era of precision medicine [13,14]. However, the mechanisms of exomiRs in regulating the dynamic crosstalk among cancer cells and CAFs and shape the TME are still elusive.…”

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.…”