E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice.
E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice.
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E1A工程改造的人脐带间充质干细胞作为腺病毒的载体和放大器抑制小鼠肝癌
DOI：
10.18632/oncotarget.10122
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发表时间：
2016-08-09
期刊：
影响因子：
--
通讯作者：
Xiong D
中科院分区：
文献类型：
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作者：
Li Z;Ye Z;Zhang X;Zhang Q;Fan D;Zhang Y;Luo HR;Yuan X;Li Z;Xiong D
基因治疗是治疗肝细胞癌（HCC）的一种有吸引力的方法。然而，有效的转基因递送仍然是一个挑战。在这项研究中，我们探索了一种新的靶向系统的基础上，人脐带来源的间充质干细胞（HUMSC），这是工程交付腺病毒到肿瘤部位，并复制和组装成新的腺病毒对肝癌。我们的结果表明，Ad-hTERTp-IL 24感染HUMSC后，LentiR.E1A感染可以特异性迁移到HepG 2肿瘤细胞，并支持腺病毒复制在体外和体内LentiR.E1A感染后36 h。Ad-hTERTp-IL 24特异性抑制HepG 2细胞生长，低剂量的5-氟尿嘧啶（5-Fu）可增强这种抑制作用，因为肿瘤细胞上科萨基腺病毒受体（CAR）和整合素ανβ3的表达水平显著增加，导致更高的病毒摄取。与未处理组相比，Ad-hTERTp-IL 24和LentiR.E1A共负载的HUMSC在体内表现出显著的抗肿瘤活性，尤其是与低剂量5-Fu联合使用时。总之，本研究提供了一种有希望的靶向基因治疗策略，依赖于HUMSC的肿瘤嗜性，以改善肿瘤患者特别是转移性疾病患者的病毒治疗结果。
Gene therapy is an attractive approach for hepatocellular carcinoma (HCC) patients. Nevertheless, efficient transgene delivery remains a challenge. In this study, we explored a new targeted system based on human umbilical cord-derived mesenchymal stem cells (HUMSCs), which were engineered to deliver adenovirus to tumor sites, and to replicate and assemble into new adenovirus against HCC. Our results showed that HUMSCs infected by Ad-hTERTp-IL24 followed by LentiR.E1A infection could specifically migrate to HepG2 tumor cells and support adenoviral replication in vitro and in vivo 36 h after LentiR.E1A infection. Ad-hTERTp-IL24 specifically inhibited HepG2 cells growth, and this inhibitory effect was enhanced by low doses of 5-fluorouracil (5-Fu), because the expression levels of coxsackie adenovirus receptor (CAR) and integrin ανβ3 on tumor cells were significantly increased, causing higher viral uptake. Compared with the no treatment groups, Ad-hTERTp-IL24 and LentiR.E1A co-loaded HUMSCs exhibited significant anti-tumor activity in vivo, particularly in combination with low doses of 5-Fu. In summary, this study provides a promising targeted gene therapeutic strategy dependent on the tumor tropism of HUMSCs, to improve the outcome of virotherapy for tumor patients especially those with metastatic diseases.