| Abstract | Abstract Cancer progression in skeletal muscle (SkM) is very rare, and mechanisms remain unclear. This study assessed the potential of SkM (myocyte)-derived EVs (C2C12-EVs) as anti-cancer agents. Using murine in vitro models, we showed that following treatment with C2C12-EVs, lung carcinoma cells failed to colonise SkM cells, and that C2C12-EVs selectively exerted apoptosis on cancer cells. Uptake of C2C12-EVs by carcinoma cells caused changes in lysosomal function and mitochondrial membrane properties inducing cell death with elevated caspase 3 and 9. The C2C12-EVs also inhibited cell proliferation, affecting cell cycle arrest at S phase and inhibited cell migration. Proteomic analysis of C2C12-EV cargoes highlighted functional enrichment pathways involved in lysozyme function, HIF-1 and PI3K-Akt signalling, regulation of actin cytoskeleton, pyruvate metabolism, platelet activation, and protein processing in ER. Decorin, a muscle cell-specific cytokine released from myocytes in response to stress, was significantly enriched in C2C12-EVs and may contribute to C2C12-EVs’ inhibitory activity on cancer cells. C2C12-EVs may suppress cancer and potentially be used as therapeutic agents for cancer metastasis. Simple Summary Skeletal muscle is rarely affected by cancer, which indicates that these muscle cells contain cancer-resistant properties. Cells release small membrane vesicles, extracellular vesicles (EVs), which are important for communication between cells, and may be protective if released from certain cells, but can also contribute to disease signalling, including in cancer. In this study, we isolated EVs from skeletal muscle cells and applied them to lung cancer cells. We found that the skeletal muscle EVs have anti-cancer signatures and stopped the cancer cells from spreading and caused them to die. Our findings highlight the potential of skeletal muscle EVs as anti-cancer agents and the importance of skeletal muscle and their EVs in healthy ageing and to protect human health in conditions when skeletal muscle mass is compromised. |
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