Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma
Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma
复制标题
DOI：
10.1016/j.canlet.2009.08.031
复制
发表时间：
2010-04-28
期刊：
影响因子：
9.7
通讯作者：
Fang, Zujun
中科院分区：
文献类型：
--
作者：
Gao, Peng;Ding, Qiang;Fang, Zujun
间充质干细胞（MSC）代表了用于递送治疗剂至癌症的新工具。细胞因子白细胞介素-12（IL-12）已在多种小鼠肿瘤模型中显示出有效的抗肿瘤活性。在这项研究中，人骨髓间充质干细胞分离，并通过表型分析和分化测定鉴定。用表达鼠IL-12的重组腺病毒载体（MSC/IL-12）稳定转导的人MSC在肾细胞癌（RCC）的小鼠异种移植模型中评估抗肿瘤活性。在体内研究之前，证实了来自腺病毒载体的转基因蛋白IL-12的表达和生物活性。将786-0细胞接种于裸鼠皮下建立肾癌裸鼠模型。MSC/IL-12单次尾静脉注射。结果表明，全身施用MSC/IL-12减少了786-0 RCC的生长并显著延长小鼠存活。这些转染的细胞经静脉注射后可归巢于肿瘤，并大量产生局部IL-12蛋白。相反，全身IL-12水平适度升高。进一步的研究表明，MSC/IL-12的抗肿瘤活性取决于在该实验环境中自然杀伤（NK）细胞和IFN-γ的存在。这些数据表明，成人MSC组成型产生IL-12，以减少RCC的生长和提高荷瘤小鼠的生存的潜力。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Mesenchymal stem cells (MSCs) represent a new tool for delivery of therapeutic agents to cancer. The cytokine interleukin-12 (IL-12) has demonstrated a potent anti-tumor activity in a variety of mouse tumor models. In this study, human MSCs were isolated from human bone marrow and identified by phenotype analysis and differentiation assays. The antitumor activity of human MSCs stably transduced with a recombinant adenoviral vector expressing the murine IL-12 (MSC/IL-12) were evaluated in a mouse xenograft model of renal cell carcinoma (RCC). Expression and bioactivity of the transgenic protein IL-12 from adenoviral vector were confirmed prior to in vivo studies. A nude mouse model of RCC was developed by subcutaneously injection of 786-0 cells into nude mice. MSC/IL-12 was injected into the lateral tail vein with single dose. Results indicated that systemic administration of MSC/IL-12 reduced the growth of 786-0 RCC and significantly prolonged mouse survival. These transfected cells could home to tumors after intravenous injection and largely produce local IL-12 protein. In contrast, systemic level of IL-12 was modestly elevated. Further studies showed that the anti-tumor activity of the MSC/IL-12 was dependent on the presence of natural killer (NK) cells and IFN-gamma in this experimental setting. These data demonstrate the potential of adult MSC constitutively producing IL-12 to reduce the growth of RCC and enhance the tumor-bearing mouse survival. (C) 2009 Elsevier Ireland Ltd. All rights reserved.