Oral administration of bovine milk-derived extracellular vesicles induces senescence in the primary tumor but accelerates cancer metastasis

It has been proposed that extracellular vesicles (EVs) from the diet can be absorbedby the intestinal tract of the consuming organism, be bioavailable in various organs,and exert phenotypic changes. Here, EVs were isolated from both raw andcommercial bovine milk and characterised by electron microscopy, nanoparticletracking analysis, Western blotting, quantitative proteomics and small RNAsequencing analysis. Orally administered bovine milk-derived EVs were able tosurvive the harsh degrading conditions of the gut of the mice and subsequently bedetected in multiple organs. Milk-derived EVs orally administered to mice implantedwith colorectal and breast cancer cells were able to reduce the primary tumorburden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVsaccelerated metastasis in breast and pancreatic cancer mice models. Proteomicsand biochemical analysis highlighted the induction of senescence and epithelial-tomesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timingof exosome administration was critical as oral administration after resection of theprimary tumor reversed the pro-metastatic effects of milk-derived EVs in breastcancer. Taken together, our study provides novel context-based and opposing role ofmilk-derived EVs as metastasis inducers and as metastasis blocker.