An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles. Cancer Cell 2019 Jan 14;35(1):33-45.e6
Date
01/16/2019Pubmed ID
30645975Pubmed Central ID
PMC6336114DOI
10.1016/j.ccell.2018.12.001Scopus ID
2-s2.0-85058438732 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.
Author List
Ortiz A, Gui J, Zahedi F, Yu P, Cho C, Bhattacharya S, Carbone CJ, Yu Q, Katlinski KV, Katlinskaya YV, Handa S, Haas V, Volk SW, Brice AK, Wals K, Matheson NJ, Antrobus R, Ludwig S, Whiteside TL, Sander C, Tarhini AA, Kirkwood JM, Lehner PJ, Guo W, Rui H, Minn AJ, Koumenis C, Diehl JA, Fuchs SYMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Disease Progression
Extracellular Vesicles
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Humans
Interferons
Lung Neoplasms
Melanoma
Mice
Neoplasm Metastasis
Oxysterols
Receptor, Interferon alpha-beta
Reserpine
Steroid Hydroxylases
THP-1 Cells
