Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors
Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors
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DOI：
10.1089/hum.2007.034
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发表时间：
2007-07-01
影响因子：
4.2
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
--
作者：
Hakkarainen, Tanja;Sarkioja, Merja;Hemminki, Akseli
由于静脉内施用的病毒的肝脏隔离，全身性腺病毒递送到肿瘤中是低效的。提高生物利用度的一个潜在解决方案是使用载体细胞，如人间充质干细胞（MSC），已被认为具有固有的肿瘤向性。在这里，我们研究了captain修饰的腺病毒感染和复制的MSC的能力。此外，在肺癌和乳腺癌的原位小鼠模型中评估了负载有溶瘤腺病毒的MSC的生物分布和肿瘤杀伤功效。在体外，硫酸乙酰肝素蛋白聚糖和α（v）β整合素靶向病毒增强基因传递到骨髓和脂肪组织来源的MSC高达11,000倍以上的腺病毒血清型5（Ad 5）。与野生型病毒相比，增殖力增强的溶瘤腺病毒显示出体外传代的MSC的细胞溶解率显著更高。在体内，静脉注射的MSC主要归巢到肺部，病毒被释放到晚期原位乳腺和肺肿瘤中，以获得治疗效果和增加存活率。当静脉注射相同剂量的病毒而不注射MSC时，仅观察到肝脏的转导。这些结果表明，骨髓间充质干细胞负载溶瘤腺病毒可能是一个有用的方法，用于提高生物利用度的溶瘤腺病毒全身给药。
Systemic adenoviral delivery into tumors is inefficient because of liver sequestration of intravenously administered virus. One potential solution for improving bioavailability is the use of carrier cells such as human mesenchymal stem cells (MSCs), which have been suggested to have inherent tumor tropism. Here we investigated the capacity of capsid-modified adenoviruses to infect and replicate in MSCs. Further, biodistribution and tumor-killing efficacy of MSCs loaded with oncolytic adenoviruses were evaluated in orthotopic murine models of lung and breast cancer. In vitro, heparan sulfate proteoglycan- and alpha(v)beta integrin-targeted viruses enhanced gene delivery to bone marrow- and adipose tissue-derived MSCs up to 11,000-fold over adenovirus serotype 5 (Ad5). Infectivity-enhanced oncolytic adenoviruses showed notably higher rates of cytolysis of in vitro-passaged MSCs in comparison with wild-type virus. In vivo, intravenously injected MSCs homed primarily to the lungs, and virus was released into advanced orthotopic breast and lung tumors for therapeutic efficacy and increased survival. When the same dose of virus was injected intravenously without MSCs, only transduction of the liver was seen. These results suggest that MSCs loaded with oncolytic adenoviruses might be a useful approach for improving the bioavailability of systemically administered oncolytic adenoviruses.