干扰素驱动的基于氧化固醇的防御机制，抵御肿瘤来源的细胞外囊泡。
An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.
机构信息
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.
出版信息
Cancer Cell. 2019 Jan 14;35(1):33-45.e6. doi: 10.1016/j.ccell.2018.12.001.
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.
摘要
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。
相似文献
1
An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.干扰素驱动的基于氧化固醇的防御机制，抵御肿瘤来源的细胞外囊泡。
Cancer Cell. 2019 Jan 14;35(1):33-45.e6. doi: 10.1016/j.ccell.2018.12.001.
2
Extracellular vesicles in cancer progression.细胞外囊泡在癌症进展中的作用。
Semin Cancer Biol. 2021 Nov;76:139-142. doi: 10.1016/j.semcancer.2021.05.032. Epub 2021 Jun 4.
3
Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma.源自淋巴管的氧化甾醇可促进黑色素瘤的抗肿瘤免疫及对免疫疗法的反应。
Nat Commun. 2025 Jan 31;16(1):1217. doi: 10.1038/s41467-025-55969-w.
4
Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.干扰素诱导的胆固醇-25-羟化酶通过产生 25-羟胆固醇广泛抑制病毒进入。
Immunity. 2013 Jan 24;38(1):92-105. doi: 10.1016/j.immuni.2012.11.005. Epub 2012 Dec 27.
5
NUPR1 packaged in extracellular vesicles promotes murine triple-negative breast cancer in a type 1 interferon-independent manner.包裹在细胞外囊泡中的NUPR1以一种不依赖1型干扰素的方式促进小鼠三阴性乳腺癌。
Extracell Vesicles Circ Nucl Acids. 2024;5(1):19-36. doi: 10.20517/evcna.2023.59. Epub 2024 Jan 15.
6
Regulation of intercellular biomolecule transfer-driven tumor angiogenesis and responses to anticancer therapies.细胞间生物分子转移驱动的肿瘤血管生成及其对癌症治疗反应的调控。
J Clin Invest. 2021 May 17;131(10). doi: 10.1172/JCI144225.
7
The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche.异种移植肿瘤内源性释放的细胞外囊泡的捕获会在转移前生态位引发炎症反应。
J Extracell Vesicles. 2023 May;12(5):e12326. doi: 10.1002/jev2.12326.
8
The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis.胆甾醇 25-羟化酶参与肠道纤维化的发生。
J Crohns Colitis. 2019 Sep 19;13(9):1186-1200. doi: 10.1093/ecco-jcc/jjz039.
9
Five-aza-2'-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells.5-氮杂-2'-脱氧胞苷诱导的胆固醇25-羟化酶基因低甲基化是骨髓增生异常综合征/白血病细胞死亡的原因。
Sci Rep. 2015 Nov 18;5:16709. doi: 10.1038/srep16709.
10
Interferon-inducible cholesterol-25-hydroxylase inhibits hepatitis C virus replication via distinct mechanisms.干扰素诱导的胆固醇25-羟化酶通过不同机制抑制丙型肝炎病毒复制。
Sci Rep. 2014 Dec 3;4:7242. doi: 10.1038/srep07242.
引用本文的文献
1
Targeted Lung Premetastasis Niche: Mechanisms, Strategies, and Application.靶向肺转移前微环境：机制、策略与应用
MedComm (2020). 2025 Jun 3;6(6):e70248. doi: 10.1002/mco2.70248. eCollection 2025 Jun.
2
Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity.微生物癌症免疫疗法可重编程造血过程，以增强髓系驱动的抗肿瘤免疫力。
Cancer Cell. 2025 May 28. doi: 10.1016/j.ccell.2025.05.002.
3
Exploring molecular and cellular mechanisms of Pre-Metastatic niche in renal cell carcinoma.探索肾细胞癌中前转移微环境的分子和细胞机制。
Mol Cancer. 2025 Apr 22;24(1):121. doi: 10.1186/s12943-025-02315-9.
4
Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma.源自淋巴管的氧化甾醇可促进黑色素瘤的抗肿瘤免疫及对免疫疗法的反应。
Nat Commun. 2025 Jan 31;16(1):1217. doi: 10.1038/s41467-025-55969-w.
5
Cholesterol: The driving force behind the remodeling of tumor microenvironment in colorectal cancer.胆固醇：结直肠癌肿瘤微环境重塑背后的驱动力。
Heliyon. 2024 Oct 15;10(23):e39425. doi: 10.1016/j.heliyon.2024.e39425. eCollection 2024 Dec 15.
6
Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.癌症诱导的远处器官系统预适应：为转移细胞构建生态位。
Nat Rev Cancer. 2024 Dec;24(12):829-849. doi: 10.1038/s41568-024-00752-0. Epub 2024 Oct 10.
7
Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies.改性 C 型利钠肽可使肿瘤血管正常化，重振抗肿瘤免疫，并改善实体瘤治疗效果。
Sci Transl Med. 2024 Aug 21;16(761):eadn0904. doi: 10.1126/scitranslmed.adn0904.
8
Extracellular vesicles and particles as mediators of long-range communication in cancer: connecting biological function to clinical applications.细胞外囊泡和颗粒作为癌症中远程通讯的介质：将生物学功能与临床应用相联系
Extracell Vesicles Circ Nucl Acids. 2023 Sep;4(3):461-485. doi: 10.20517/evcna.2023.37. Epub 2023 Aug 16.
9
Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.肿瘤微环境中的胆固醇代谢：癌症特征与治疗机遇
Int J Biol Sci. 2024 Mar 17;20(6):2044-2071. doi: 10.7150/ijbs.92274. eCollection 2024.
10
Extracellular vesicle-mediated pre-metastatic niche formation via altering host microenvironments.细胞外囊泡介导的前转移龛形成通过改变宿主微环境。
Front Immunol. 2024 Mar 1;15:1367373. doi: 10.3389/fimmu.2024.1367373. eCollection 2024.
本文引用的文献
1
Generation and testing of clinical-grade exosomes for pancreatic cancer.生成和测试胰腺癌的临床级别的外泌体。
JCI Insight. 2018 Apr 19;3(8). doi: 10.1172/jci.insight.99263.
2
Immunoaffinity-based isolation of melanoma cell-derived exosomes from plasma of patients with melanoma.基于免疫亲和从黑色素瘤患者血浆中分离黑色素瘤细胞衍生的外泌体。
J Extracell Vesicles. 2018 Feb 15;7(1):1435138. doi: 10.1080/20013078.2018.1435138. eCollection 2018.
3
The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells.胆固醇代谢物27-羟基胆固醇通过作用于免疫细胞促进乳腺癌转移。
Nat Commun. 2017 Oct 11;8(1):864. doi: 10.1038/s41467-017-00910-z.
4
A unique gene expression signature is significantly differentially expressed in tumor-positive or tumor-negative sentinel lymph nodes in patients with melanoma.一种独特的基因表达特征在黑色素瘤患者的肿瘤阳性或肿瘤阴性前哨淋巴结中存在显著差异表达。
Melanoma Res. 2017 Oct;27(5):429-438. doi: 10.1097/CMR.0000000000000383.
5
25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.25-羟基胆固醇在小鼠模型中保护宿主免受寨卡病毒感染及其相关的小头畸形。
Immunity. 2017 Mar 21;46(3):446-456. doi: 10.1016/j.immuni.2017.02.012. Epub 2017 Mar 14.
6
Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment.干扰素受体失活促进免疫豁免肿瘤微环境的形成。
Cancer Cell. 2017 Feb 13;31(2):194-207. doi: 10.1016/j.ccell.2017.01.004.
7
Extracellular vesicle docking at the cellular port: Extracellular vesicle binding and uptake.细胞端口处的细胞外囊泡对接：细胞外囊泡的结合与摄取。
Semin Cell Dev Biol. 2017 Jul;67:48-55. doi: 10.1016/j.semcdb.2017.01.002. Epub 2017 Jan 16.
8
Exosomes: Key mediators of metastasis and pre-metastatic niche formation.外泌体：转移和转移前生态位形成的关键介质。
Semin Cell Dev Biol. 2017 Jul;67:3-10. doi: 10.1016/j.semcdb.2017.01.004. Epub 2017 Jan 8.
9
Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis.癌症中的细胞外囊泡：转移的细胞间介质
Cancer Cell. 2016 Dec 12;30(6):836-848. doi: 10.1016/j.ccell.2016.10.009.
10
Cancer-derived extracellular vesicles: the 'soil conditioner' in breast cancer metastasis?癌症衍生的细胞外囊泡：乳腺癌转移中的“土壤改良剂”？
Cancer Metastasis Rev. 2016 Dec;35(4):669-676. doi: 10.1007/s10555-016-9639-8.
Zotero 插件