Extracellular vesicles in cancer progression.

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.