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从恶性间皮瘤癌症相关成纤维细胞中分离出的细胞外囊泡诱导健康间皮细胞发生致癌变化。

Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells.

机构信息

MRC Toxicology Unit, University of Cambridge, Tennis Court Rd., Cambridge CB2 1QR, UK.

UHL NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK.

出版信息

Int J Mol Sci. 2022 Oct 18;23(20):12469. doi: 10.3390/ijms232012469.

DOI:10.3390/ijms232012469
PMID:36293328
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9604431/
Abstract

Malignant mesothelioma is an aggressive tumour of the pleura (MPM) or peritoneum with a clinical presentation at an advanced stage of the disease. Current therapies only marginally improve survival and there is an urgent need to identify new treatments. Carcinoma-associated fibroblasts (CAFs) represent the main component of a vast stroma within MPM and play an important role in the tumour microenvironment. The influence of CAFs on cancer progression, aggressiveness and metastasis is well understood; however, the role of CAF-derived extracellular vesicles (CAF-EVs) in the promotion of tumour development and invasiveness is underexplored. We purified CAF-EVs from MPM-associated cells and healthy dermal human fibroblasts and examined their effect on cell proliferation and motility. The data show that exposure of healthy mesothelial cells to EVs derived from CAFs, but not from normal dermal human fibroblasts (NDHF) resulted in activating pro-oncogenic signalling pathways and increased proliferation and motility. Consistent with its role in suppressing Yes-Associated Protein (YAP) activation (which in MPM is a result of Hippo pathway inactivation), treatment with Simvastatin ameliorated the pro-oncogenic effects instigated by CAF-EVs by mechanisms involving both a reduction in EV number and changes in EV cargo. Collectively, these data determine the significance of CAF-derived EVs in mesothelioma development and progression and suggest new targets in cancer therapy.

摘要

恶性间皮瘤是一种侵袭性胸膜（MPM）或腹膜肿瘤，在疾病的晚期出现临床症状。目前的治疗方法只能略微提高生存率，因此迫切需要寻找新的治疗方法。癌相关成纤维细胞（CAFs）是 MPM 中大量基质的主要成分，在肿瘤微环境中发挥重要作用。CAFs 对癌症进展、侵袭性和转移的影响已经得到充分理解；然而，CAF 衍生的细胞外囊泡（CAF-EVs）在促进肿瘤发展和侵袭性方面的作用仍未得到充分探索。我们从 MPM 相关细胞和健康皮肤成纤维细胞中纯化了 CAF-EVs，并研究了它们对细胞增殖和迁移的影响。数据表明，暴露于源自 CAFs 的 EVs 而不是源自正常皮肤成纤维细胞（NDHF）会激活致癌信号通路，从而增加增殖和迁移。与它在抑制 Yes-Associated Protein（YAP）激活中的作用一致（在 MPM 中，这是 Hippo 通路失活的结果），辛伐他汀通过减少 EV 数量和改变 EV 货物的机制来减轻 CAF-EVs 引发的致癌作用。总之，这些数据确定了 CAF 衍生的 EVs 在间皮瘤发生和发展中的重要性，并为癌症治疗提供了新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b0b/9604431/583a14f3e009/ijms-23-12469-g005.jpg
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