Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells.
Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells.
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DOI：
10.3390/ijms232012469
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发表时间：
2022-10-18
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
恶性间皮瘤是一种侵袭性的胸膜或腹膜肿瘤，临床表现为晚期。目前的治疗方法只能略微提高存活率，迫切需要找到新的治疗方法。肿瘤相关成纤维细胞(CAF)是MPM中大量间质的主要成分，在肿瘤微环境中发挥着重要作用。CAF对肿瘤进展、侵袭和转移的影响已为人们所熟知，然而，CAF衍生的细胞外小泡(CAF-EV)在促进肿瘤发展和侵袭中的作用尚未被充分研究。我们从MPM相关细胞和健康人真皮成纤维细胞中纯化了CAF-EV，并检测了它们对细胞增殖和运动的影响。数据显示，健康的间皮细胞暴露于来自CAF的EV，而不是来自正常真皮人成纤维细胞(NDHF)的EV，导致激活致癌信号通路，并增加增殖和运动。与其抑制YAP激活(在MPM中是河马途径失活的结果)的作用一致，辛伐他汀治疗通过减少EV数量和EV货物变化来改善CAF-EVS引发的促肿瘤效应。总而言之，这些数据决定了CAF来源的EVS在间皮瘤发生和发展中的重要性，并提出了癌症治疗的新靶点。
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.
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影响因子：
28.2
作者：
Hmeljak J;Sanchez-Vega F;Hoadley KA;Shih J;Stewart C;Heiman D;Tarpey P;Danilova L;Drill E;Gibb EA;Bowlby R;Kanchi R;Osmanbeyoglu HU;Sekido Y;Takeshita J;Newton Y;Graim K;Gupta M;Gay CM;Diao L;Gibbs DL;Thorsson V;Iype L;Kantheti H;Severson DT;Ravegnini G;Desmeules P;Jungbluth AA;Travis WD;Dacic S;Chirieac LR;Galateau-Sallé F;Fujimoto J;Husain AN;Silveira HC;Rusch VW;Rintoul RC;Pass H;Kindler H;Zauderer MG;Kwiatkowski DJ;Bueno R;Tsao AS;Creaney J;Lichtenberg T;Leraas K;Bowen J;TCGA Research Network;Felau I;Zenklusen JC;Akbani R;Cherniack AD;Byers LA;Noble MS;Fletcher JA;Robertson AG;Shen R;Aburatani H;Robinson BW;Campbell P;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
3.7
作者：
Bansal D;Undela K;D'Cruz S;Schifano F
通讯作者：
Schifano F
影响因子：
11.2
作者：
Jube S;Rivera ZS;Bianchi ME;Powers A;Wang E;Pagano I;Pass HI;Gaudino G;Carbone M;Yang H
通讯作者：
Yang H
影响因子：
8
作者：
Ito, T-K;Ishii, G.;Ochiai, A.
通讯作者：
Ochiai, A.
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.