Melanoma-Derived Exosomes Endow Fibroblasts with an Invasive Potential via miR-21 Target Signaling Pathway

BACKGROUND: Tumor-derived exosomes are messengers that participate in tumor progression. Fibroblasts are associated with the metastasis of cancer depending on their cellular plasticity. We hypothesize that tumor-derived exosomes endow the fibroblasts in tumor microenvironment with invasive phenotype to the benefit of tumor metastasis. MATERIALS AND METHODS: Exosomes derived from B16-F10 cells were identified by nanoparticle tracking analyzer (NTA), dynamic light scattering (DLS), Western blot (WB), and transmission electron microscopy (TEM). Cell invasion and migration assays were performed using the xCELLigence real-time cell analyzer (RTCA). Role of tumor-derived exosomal miR-21 in cell invasion was determined by qPCR. RESULTS: The invasion analysis showed that exosome-treated fibroblast cells had greater invasive capability as compared to untreated fibroblast cells, with the higher expressions of MMP2 and MMP9. miR-21 is at least partially responsible for this effect. After ingestion of melanoma-derived exosomes during incubation, mouse embryonic fibroblasts cells emerged cellular invasiveness with the presentation of a marked increase in miR-21 expression. MiR-21 promoted invasion of fibroblasts by down-regulation of tissue inhibitor of metalloproteinase 3 (TIMP3) expression and increasing of matrix metalloprotein (MMP) expression in fibroblast cells via melanoma-derived exosomes in a time-dependent manner. CONCLUSION: Our results suggest that tumor-derived exosomes may facilitate stromal fibroblasts an aggressive phenotype to equip the tumor progression.