Oral administration of bovine milk-derived extracellular vesicles induces senescence in the primary tumor but accelerates cancer metastasis
journal contributionposted on 2021-12-14, 05:42 authored by Monisha Samuel, Hewafonsekage FonsekaHewafonsekage Fonseka, Rahul SanwlaniRahul Sanwlani, Lahiru GangodaLahiru Gangoda, SH Chee, Shivakumar KeerthikumarShivakumar Keerthikumar, A Spurling, Sai Vara Prasad ChittiSai Vara Prasad Chitti, D Zanker, CS Ang, Atukoralage Atukorala, Taeyoung KangTaeyoung Kang, Sanjay ShahiSanjay Shahi, Akbar Lulu MarzanAkbar Lulu Marzan, C Nedeva, C Vennin, MC Lucas, Lesley SimLesley Sim, D Herrmann, Mohashin PathanMohashin Pathan, David ChisangaDavid Chisanga, SC Warren, Kening ZhaoKening Zhao, Nidhi Abraham, S Anand, S Boukouris, Christopher AddaChristopher Adda, Lanzhou JiangLanzhou Jiang, Tanmay ShekharTanmay Shekhar, N Baschuk, Christine HawkinsChristine Hawkins, Amelia JohnstonAmelia Johnston, Jacqueline OrianJacqueline Orian, Nick HoogenraadNick Hoogenraad, Ivan PoonIvan Poon, Andrew HillAndrew Hill, Markandeya JoisMarkandeya Jois, P Timpson, Belinda ParkerBelinda Parker, Suresh MathivananSuresh Mathivanan
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.