Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222

Abstract

Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

Comparative analysis of microRNA expression profiles between A549, A549/DDP and their respective exosomes

“…For example, Shanliang Zhong et al [20] found in breast cancer that a number of miRNAs were concentrated in exosomes and participate in the process of drug resistance. Yu DD et al [21] demonstrated that exosomes can effectively transmitted drug resistance in breast cancer, and the delivery of miR-222 via exosomes can serve as the mechanism. However, there is little research on the role of exosomal miRNAs in the process of lung cancer cells to cisplatin(DDP) resistance.…”

Exosome‑mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR‑21

“…In addition, studies have identified a close association between exosomes and drug resistance in various types of cancer, including breast (9,22), ovarian (23) and prostate (24) cancer, which suggests that drug resistance in lung cancer cells may be acquired via exosomes. Cisplatin exposure may increase exosome secretion and the interaction of these secreted exosomes with other cancer cells may increase the resistance of A549 cells to cisplatin (10).…”

Exosomes as Reconfigurable Therapeutic Systems

“…For instance, melanoma-derived exosomes have been shown to transfer the C-Met oncoprotein to bone marrow progenitor cells, inducing vascular leakiness at pre-metastatic sites, and promoting metastasis in mouse tumor models [54]. They also appear to influence drug resistance; for instance, exosomes isolated from an adriamycin-resistant breast cancer cell lines have been found to transfer drug resistance to drug-sensitive human breast cancer cell lines upon delivery of miR-222 in vitro [55]. An association between exosomes and obesity-related insulin resistance has also been reported; in this study, adipocyte-derived exosomes were found to activate adipose-resident macrophages and secrete inflammatory cytokines (L-6 and TNF-alpha), leading to insulin resistance in a ob/ob obesity mouse model [56].…”