Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
Oncogene. 2010 May 13;29(19):2784-94. doi: 10.1038/onc.2010.38. Epub 2010 Mar 1.
The poor outcome of cancer gene therapy in clinical trials relates in part to insufficient gene delivery to tumor sites. Mesenchymal stem cells (MSCs) represent a new tool for the delivery of therapeutic agents to tumor cells. This study used an orthotopic nude mice model of hepatocellular carcinoma (HCC) to evaluate the potential of genetically modified human MSCs (hMSCs), to function as an effective delivery vehicle for therapeutic genes. hMSCs derived from the bone marrow were efficiently engineered to express human pigment epithelium-derived factor (PEDF) by lentiviral transduction, then tested in vitro for high-level expression and bioactivity of the transgenic protein. The preferential homing of hMSCs toward HCC was confirmed by in vitro and in vivo migration assays. in vivo efficacy experiments showed that intravenous (i.v.) injection of PEDF-expressing hMSCs significantly suppressed both the growth of primary liver tumors and the development of pulmonary metastases. Moreover, hMSCs-based PEDF gene delivery moderately increased the systemic levels of human PEDF. Immunohistochemistry of primary liver tumors demonstrated lower microvessel density in mice treated with hMSCs-PEDF than in control mice. This is the first study to show the potential of hMSCs as an effective delivery vehicle for therapeutic genes in the treatment of HCC.
癌症基因治疗临床试验的不良结果在一定程度上与肿瘤部位的基因传递不足有关。间充质干细胞（MSCs）为将治疗剂递送到肿瘤细胞提供了一种新的工具。本研究使用肝癌（HCC）的原位裸鼠模型，评估了基因修饰的人 MSCs（hMSCs）作为治疗基因有效传递载体的潜力。通过慢病毒转导，从骨髓中分离出的 hMSCs 被有效地工程化为表达人色素上皮衍生因子（PEDF），然后在体外测试转基因蛋白的高水平表达和生物活性。体外和体内迁移实验证实了 hMSCs 对 HCC 的优先归巢。体内疗效实验表明，表达 PEDF 的 hMSCs 的静脉（i.v.）注射显著抑制了原发性肝癌的生长和肺转移的发展。此外，基于 hMSCs 的 PEDF 基因传递适度增加了人 PEDF 的系统水平。对原发性肝癌的免疫组织化学分析表明，与对照组小鼠相比，用 hMSCs-PEDF 治疗的小鼠的微血管密度较低。这是第一项表明 hMSCs 作为治疗 HCC 的治疗基因有效传递载体的潜力的研究。
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