Abstract
The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors.
Highlights
The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable
EVs were isolated from raw milk (RM) and commercial milk (CM) samples by differential centrifugation coupled with ultracentrifugation
Western blotting of whole milk (WM) and CM EVs for high abundant milk protein casein and EV-enriched protein TSG101 confirmed the depletion of casein and enrichment of EVs in the isolated fractions (Supplementary Fig. 1b, c)
Summary
The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. The concept of cross-kingdom communication was further strengthened when high levels of exogenous plant miR159 in human sera negatively correlated with breast cancer incidence and progression[3] In corroboration with this observation, oral delivery of miR159 significantly reduced xenograft breast tumor burden. Being an immensely intricate secretory product, designed for regulation of neonatal development, its persistent consumption throughout the lifespan may have substantial implications on human health[12,16] Both raw as well as CM have been shown to contain EVs that carry a cargo rich in RNAs and proteins[11,17]. Despite reduction in primary tumor size, milk-derived EVs augmented metastasis in various cancer models raising serious implications the diet may have on the fatal steps of this disease These results highlight the role of milk-derived EVs in cross-species communication and their significant context-dependent role in regulating cancer progression and metastasis
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