Mesenchymal stem cells deliver and release conditionally replicative adenovirus depending on hepatic differentiation to eliminate hepatocellular carcinoma cells specifically
Mesenchymal stem cells deliver and release conditionally replicative adenovirus depending on hepatic differentiation to eliminate hepatocellular carcinoma cells specifically
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间充质干细胞根据肝分化递送和释放条件复制腺病毒，特异性消除肝细胞癌细胞
DOI：
10.1016/j.canlet.2016.07.019
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发表时间：
2016
期刊：
影响因子：
9.7
通讯作者：
Xiong Dongsheng
中科院分区：
文献类型：
--
作者：
Yuan Xiangfei;Zhang Qing;Li Zhenzhen;Zhang Xiaolong;Bao Shiqi;Fan Dongmei;Ru Yongxin;Dong Shuxu;Zhang Yizhi;Zhang Yanjun;Ye Zhou;Xiong Dongsheng
目前，肝细胞癌术后残留和转移灶的清除是一个关键的挑战。（HCC）。溶瘤腺病毒疗法是一种有吸引力的癌症治疗方式;然而，关于其静脉内施用仍然存在困难。本研究的目的是开发一种具有巨大潜力的靶向治疗系统，以克服肝癌术后残留和转移。在该系统中，我们构建了一种负载人脐带间充质干细胞的条件复制型腺病毒（CRAd），其中CRAd含有由甲胎蛋白启动子和microRNA-122靶序列双重调控的腺病毒E1 A基因。当HUMSC归巢到肿瘤部位并在肿瘤微环境中分化为肝细胞样细胞时，CRAd被包装并严格释放到肿瘤局部。随后，CRAd.在感染后调节下选择性地裂解肿瘤细胞。本研究显示了CRAd对肝癌细胞的特异性溶瘤作用以及体外分化的HUMSC产生CRAd。进一步证实了HUMSC在原位或异位肝癌微环境中的肝细胞样转化。最后，该治疗系统对原位和皮下肝异种移植肿瘤模型小鼠均表现出显着的肿瘤抑制作用，对正常器官的毒性较小。研究结果表明，这种靶向治疗策略是解决肝癌术后残留和转移问题的一种有希望的method.to。
Currently, it is a key challenge to remove the postsurgical residuals and metastasis of hepatocellular carcinoma.(HCC). Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer; however,.the difficulty remains regarding its intravenous administration. The aim of this study was to develop a.targeted therapeutic system which has great potential to overcome the postsurgical residuals and metastasis.of HCC. In this system, we developed a conditionally replicative adenovirus (CRAd) loaded on.human umbilical cord-derived mesenchymal stem cells (HUMSCs), in which the CRAd contained an adenovirus.E1A gene dual regulated by α-fetoprotein promoter and microRNA-122 target sequence. When.HUMSCs homed to the tumor sites and differentiated into hepatocyte-like cells within tumor microenvironment,.the CRAds were packaged and released strictly to the local tumor. Subsequently, the CRAd.lysed tumor cells selectively with the post-infection regulation. The study showed the specific oncolytic.effect of the CRAd to HCC cells and the production of the CRAd by differentiated HUMSCs in vitro..Furthermore, we proved the hepatocyte-like transformation of HUMSC in the microenvironment of orthotopic.or heterotopic hepatoma. Finally, this therapeutic system exhibited dramatic tumor inhibition.on both orthotopic and subcutaneous hepatic xenograft tumor model mice with less toxicity on normal.organs. The study results have demonstrated that this targeted therapeutic strategy is a promising method.to resolve the problem of postsurgical residuals and metastasis of HCC.