Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice
Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice
复制标题
DOI：
10.1038/onc.2010.38
复制
发表时间：
2010-05-01
期刊：
影响因子：
8
通讯作者：
Wang, X.
中科院分区：
文献类型：
--
作者：
Gao, Y.;Yao, A.;Wang, X.
癌症基因治疗在临床试验中的不良结果部分与肿瘤部位的基因递送不足有关。间充质干细胞（MSC）代表了一种新的工具，用于输送治疗剂的肿瘤细胞。本研究使用原位裸小鼠肝细胞癌（HCC）模型来评估遗传修饰的人间充质干细胞（hMSCs）作为治疗基因的有效递送载体的潜力。通过慢病毒转导的方法将来源于骨髓的hMSCs高效地工程化以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。通过体外和体内迁移试验证实了hMSCs向HCC的优先归巢。体内功效实验表明，静脉内（i. v.）注射表达PEDF的hMSC显著抑制了原发性肝肿瘤的生长和肺转移的发展。此外，基于hMSC的PEDF基因递送适度增加了人PEDF的全身水平。原发性肝肿瘤的免疫组织化学显示用hMSCs-PEDF处理的小鼠中的微血管密度低于对照小鼠。这是第一项研究显示hMSCs作为治疗基因在HCC治疗中的有效递送载体的潜力。Oncogene（2010）29，2784-2794; doi：10.1038/onc.2010.38; 2010年3月1日在线发表
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. Oncogene (2010) 29, 2784-2794; doi: 10.1038/onc.2010.38; published online 1 March 2010