Treatment of Mesenchymal Stem Cell-Derived Extracellular Vesicles with Extract of Cultured Lentinula edodes Modulates Breast Cancer Stem Cells and MicroRNA Reprogramming

Breast carcinoma represents the most frequent malignancy in women in Canada, and intrinsic or acquired drug resistance significantly increases the risk of recurrence and metastasis. Although front-line therapy is multimodal, chemoresistance remains a major hurdle in treatment and therapy, and the intake of natural compounds resulting from fermentation processes is currently considered an effective strategy to overcome this problem. This study investigated the effect of extracellular vesicles (EVs) from Mesenchymal Stromal/stem cells (MSCs) pretreated with cultured Lentinula edodes extract (AHCC) on reducing chemoresistance and modulating microRNAs in the MCF-7 and MCF-7/DOX cell lines. EV characterization was performed using nanoparticle tracking analysis, and microRNAs and the formation of cancer stem cells were studied. The miRNA analysis revealed that AHCC significantly downregulated oncogenic miR-155 but upregulated the tumor-suppressive microRNAs miR-34a, miR-Let7a, and miR-200c. In vitro experiments showed inhibition of cancer stem cell proliferation after challenging the cells with AHCC-pretreated EVs. Conclusion: Our data demonstrated that AHCC may contribute to modulation of the tumor microenvironment, thus influencing the development of cancer stem cells.