| Literature DB >> 30645975 |
Angelica Ortiz1, Jun Gui1, Farima Zahedi1, Pengfei Yu1, Christina Cho1, Sabyasachi Bhattacharya1, Christopher J Carbone1, Qiujing Yu1, Kanstantsin V Katlinski1, Yuliya V Katlinskaya1, Simran Handa1, Victor Haas1, Susan W Volk2, Angela K Brice3, Kim Wals4, Nicholas J Matheson4, Robin Antrobus4, Sonja Ludwig5, Theresa L Whiteside6, Cindy Sander7, Ahmad A Tarhini7, John M Kirkwood7, Paul J Lehner4, Wei Guo8, Hallgeir Rui9, Andy J Minn10, Constantinos Koumenis10, J Alan Diehl11, Serge Y Fuchs12.
Abstract
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.Entities:
Keywords: 25-hydroxycholesterol; IFNAR1; adjuvant therapy; exosomes; extracellular vesicles; interferon; melanoma; metastasis; pre-metastatic niche; reserpine
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Year: 2019 PMID： 30645975 PMCID： PMC6336114 DOI： 10.1016/j.ccell.2018.12.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743