Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells
Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells
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DOI：
10.1038/sj.cgt.7701079
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发表时间：
2007-11-01
影响因子：
6.4
通讯作者：
Saijo, Y.
中科院分区：
文献类型：
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作者：
Kanehira, M.;Xin, H.;Saijo, Y.
大多数晚期实体瘤转移到不同的器官。然而，目前还没有对多发性肿瘤有效的基因治疗方法。由于骨髓间充质干细胞(MSCs)的一个独特特征是向肿瘤组织迁移，我们想确定MSCs是否可以作为靶向多种肿瘤的基因治疗载体。首先，我们证实在结肠-26(C-26)肺转移模型中，小鼠MSCs优先迁移到肺的多个肿瘤。将肝细胞生长因子(HGF)拮抗剂NK4通过带有RGD基序的腺病毒载体高效转导MSCs。经尾静脉全身给药后，表达NK4的MSCs(NK4-MSCs)对C-26肺转移模型的肺转移有明显的抑制作用。NK4-MSCs通过抑制肿瘤相关血管生成和淋巴管生成，诱导肿瘤细胞凋亡，显著延长C-26荷瘤小鼠的存活时间。基于MSC的基因治疗不会引起常规腺病毒载体所致的严重不良反应。这些结果表明，MSCs可以作为靶向多发肺转移瘤的基因治疗载体。
Most advanced solid tumors metastasize to different organs. However, no gene therapy effective for multiple tumors has yet been developed. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting multiple tumors. First, we confirmed that mouse MSCs preferentially migrate to multiple tumors of the lung in the Colon-26 (C-26) lung metastasis model. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF), by an adenoviral vector with an RGD motif. MSCs expressing NK4 (NK4-MSCs) strongly inhibited development of lung metastases in the C-26 lung metastasis model after systemic administration via a tail vein. Treatment with NK4-MSCs significantly prolonged survival of the C-26-tumor-bearing mice by inhibiting tumor-associated angiogenesis and lymphangiogenesis and inducing apoptosis of the tumor cells. MSC-based gene therapy did not induce the severe adverse effects induced by conventional adenoviral vectors. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting multiple lung metastatic tumors.