Small extracellular vesicles ameliorate peripheral neuropathy and enhance chemotherapy of oxaliplatin on ovarian cancer.
Small extracellular vesicles ameliorate peripheral neuropathy and enhance chemotherapy of oxaliplatin on ovarian cancer.
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DOI：
10.1002/jev2.12073
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发表时间：
2021-03
影响因子：
16
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Zhang Y;Li C;Qin Y;Cepparulo P;Millman M;Chopp M;Kemper A;Szalad A;Lu X;Wang L;Zhang ZG
化疗引起的周围神经病变（CIPN）尚无有效的治疗方法。小细胞外囊泡（sEV）促进细胞间通讯并介导神经功能和肿瘤进展。我们发现，用脑内皮细胞来源的sEV（CEC-sEV）联合化疗药物奥沙利铂治疗携带卵巢肿瘤的小鼠，通过减少奥沙利铂损伤的髓鞘形成和坐骨神经的神经纤维，显著降低了奥沙利铂诱导的CIPN，并通过减小肿瘤大小显著增强了奥沙利铂的化疗作用。联合治疗显著增加了一组富含sEV货物的miRNA，但显著减少了坐骨神经和肿瘤组织中奥沙利铂增加的蛋白质。生物信息学分析显示，改变的miRNAs和蛋白质形成了两个不同的网络，分别调节神经病变和肿瘤生长。腹腔内施用的CEC-sEV被坐骨神经和癌细胞的轴突内化。CEC-sEV货物miRNA的减少消除了CEC-sEV对奥沙利铂抑制的轴突生长和卵巢癌细胞中抗癌作用的放大的影响，表明受体细胞中miRNA和蛋白质网络的改变有助于CEC-sEV对CIPN的治疗作用。总之，本研究表明，CEC-sEV抑制了CIPN，并增强了荷卵巢肿瘤小鼠中奥沙利铂的化疗。
There are no effective treatments for chemotherapy induced peripheral neuropathy (CIPN). Small extracellular vesicles (sEVs) facilitate intercellular communication and mediate nerve function and tumour progression. We found that the treatment of mice bearing ovarian tumour with sEVs derived from cerebral endothelial cells (CEC‐sEVs) in combination with a chemo‐drug, oxaliplatin, robustly reduced oxaliplatin‐induced CIPN by decreasing oxaliplatin‐damaged myelination and nerve fibres of the sciatic nerve and significantly amplified chemotherapy of oxaliplatin by reducing tumour size. The combination therapy substantially increased a set of sEV cargo‐enriched miRNAs, but significantly reduced oxaliplatin‐increased proteins in the sciatic nerve and tumour tissues. Bioinformatics analysis revealed the altered miRNAs and proteins formed two distinct networks that regulate neuropathy and tumour growth, respectively. Intravenously administered CEC‐sEVs were internalized by axons of the sciatic nerve and cancer cells. Reduction of CEC‐sEV cargo miRNAs abolished the effects of CEC‐sEVs on oxaliplatin‐inhibited axonal growth and on amplification of the anti‐cancer effect in ovarian cancer cells, suggesting that alterations in the networks of miRNAs and proteins in recipient cells contribute to the therapeutic effect of CEC‐sEVs on CIPN. Together, the present study demonstrates that CEC‐sEVs suppressed CIPN and enhanced chemotherapy of oxaliplatin in the mouse bearing ovarian tumour.
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影响因子：
8
作者：
Fang D;Chen H;Zhu JY;Wang W;Teng Y;Ding HF;Jing Q;Su SB;Huang S
通讯作者：
Huang S
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
--
作者：
Addington, James;Freimer, Miriam
通讯作者：
Freimer, Miriam
影响因子：
4.8
作者：
Gordillo, Gayle M.;Biswas, Ayan;Sen, Chandan K.
通讯作者：
Sen, Chandan K.
DOI：
10.1111/j.1742-4658.2010.07818.x
发表时间：
2010-10
期刊：
The FEBS journal
影响因子：
--
作者：
Buller B;Liu X;Wang X;Zhang RL;Zhang L;Hozeska-Solgot A;Chopp M;Zhang ZG
通讯作者：
Zhang ZG