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

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.

Repurposing of Antibiotic Sulfisoxazole Inhibits Lipolysis in Pre-Clinical Model of Cancer-Associated Cachexia

“…Recently, repurposing of an FDA-approved oral antibiotic, sulfisoxazole (SFX), in pre-clinical breast cancer models demonstrated its anti-tumour and anti-metastatic effects [ 30 ]. It has been proposed that SFX treatment reduces the release of extracellular vesicles, small membranous vesicles released by cells [ 31 , 32 ], and thereby reduces metastasis of these cancer cells. However, another study failed to confirm this finding that SFX reduces the release of extracellular vesicles by cancer cells [ 33 ].…”

Skimmed Bovine Milk-Derived Extracellular Vesicles Isolated via “Salting-Out”: Characterizations and Potential Functions as Nanocarriers

“…The BM-EVs precipitated by ammonium sulfate have several characterizations that were consistent with previous knowledge, including nanoscale spherical shape, proteins, and nucleic acid cargo. The effects of acidification on BM-EVs and their resistance against digestion have been studied previously, suggesting that BM-EVs hold a stable property under harsh degrading conditions (20)(21)(22). In our study, BM-EVs in the solution of HCl and ammonium sulfate could be recovered using centrifugal ultrafiltration devices, which showed their ability to withstand high ionic strength as both chemicals are adequately soluble in water.…”

The Roles of Extracellular Vesicles in Malignant Melanoma

“…The injected EVs derived from colon cancer through the tail vein of NOD.CB17-Prkdc scid /NcrCrlBltw mice determined neoplastic transformation and metastases in the lungs of the mice [87]. Another study proved that the timing of EV administration is as critical as that of oral administration after resection of the primary tumor reversed the pro-metastatic effects of milk-derived EVs in breast cancer models [88]. EVs from a highly metastatic clonal variant of the osteosarcoma cell line were internalized by a poorly metastatic clonal variant of the same cell line and induced a migratory and invasive phenotype.…”