Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cancer Cell. 2019 Jan 14;35(1):33-45.e6. doi: 10.1016/j.ccell.2018.12.001.
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.
肿瘤衍生的细胞外囊泡 (TEV)“教育”健康细胞以促进转移。我们发现黑色素瘤 TEV 下调了 I 型干扰素 (IFN) 受体和 IFN 诱导的胆固醇 25-羟化酶 (CH25H) 的表达。CH25H 产生 25-羟胆固醇，抑制 TEV 摄取。黑色素瘤患者白细胞中的 CH25H 水平较低与预后不良相关。不能下调 IFN 受体和 Ch25h 的小鼠对 TEV 摄取、TEV 诱导的前转移龛和黑色素瘤肺转移具有抗性；然而，Ch25h 的消融逆转了这些表型。一种抗高血压药物利血平抑制了 TEV 的摄取，并破坏了 TEV 诱导的前转移龛和黑色素瘤肺转移的形成。这些结果表明 CH25H 在防御 TEV 对正常细胞的“教育”方面的重要性，并主张在辅助黑色素瘤治疗中使用利血平。
