Cancer cells release a variety of factors that contribute to the alteration of proximal and distal tissues to promote metastasis. Recent studies have demonstrated that aggressive cancer cells release extracellular vesicles with higher protein content and in excess than extracellular vesicles isolated from patients with less aggressive disease or healthy individuals. We found that melanoma tumor-derived extracellular vesicles (TEV) downregulate type I interferon receptor subunit 1 (IFNAR1), suppress expression of the interferon stimulated gene cholesterol 25-hydroxylase (CH25H). Loss of CH25H is observed in the leukocytes from melanoma patients, which correlated with metastasis and poor survival. Similarly, mice also exhibit loss of IFNAR1 following TEV administration. Moreover, loss of CH25H increased TEV uptake and TEV-induced pre metastatic niche and lung metastasis. Use of the anti-hypertensive drug, reserpine, mimicked the effects of the CH25H product 25-hydroxycholesterol to suppress TEV uptake and TEV-mediated tumor growth, pre-metastatic niche formation, and lung metastasis. These results suggest the importance of CH25H in suppressing TEV mediate cancer progression and importance of developing strategies to suppress TEV uptake and TEV-mediated disease progression.

癌细胞释放多种因子，这些因子有助于改变近端和远端组织以促进转移。最近的研究表明，侵袭性癌细胞释放的细胞外囊泡具有更高的蛋白质含量，并且比从侵袭性较小的疾病患者或健康个体中分离出的细胞外囊泡更多。我们发现黑色素瘤来源的细胞外囊泡 (TEV) 下调 I 型干扰素受体亚基 1 (IFNAR1)，抑制干扰素刺激基因胆固醇 25-羟化酶 (CH25H) 的表达。在黑色素瘤患者的白细胞中观察到 CH25H 的缺失，这与转移和较差的存活率相关。同样，小鼠在 TEV 给药后也表现出 IFNAR1 的丢失。而且，CH25H 的缺失增加了 TEV 摄取和 TEV 诱导的转移前生态位和肺转移。使用抗高血压药物利血平模拟 CH25H 产物 25-羟基胆固醇抑制 TEV 摄取和 TEV 介导的肿瘤生长、转移前生态位形成和肺转移的作用。这些结果表明 CH25H 在抑制 TEV 介导的癌症进展中的重要性以及制定抑制 TEV 摄取和 TEV 介导的疾病进展的策略的重要性。