Melanoma-derived exosomes endow fibroblasts with an invasive potential via mir-21 target signaling pathway

Abstract

Background: Tumor-derived exosomes are messengers that participate in tumor progres-sion. 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 nano-particle tracking analyzer (NTA), dynamic light scattering (DLS), Western blot (WB), and transmission electron microscopy (TEM). Cell invasion and migration assays were per-formed 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 metalloprotei-nase 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 fibro-blasts an aggressive phenotype to equip the tumor progression.