Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
Cancer Lett. 2010 Apr 28;290(2):157-66. doi: 10.1016/j.canlet.2009.08.031. Epub 2009 Sep 27.
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 anti-tumor 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.
间质干细胞（MSCs）代表了一种将治疗剂递送到癌症的新工具。细胞因子白细胞介素-12（IL-12）在多种小鼠肿瘤模型中表现出强大的抗肿瘤活性。在这项研究中，从人骨髓中分离出人 MSCs，并通过表型分析和分化测定进行鉴定。用表达小鼠 IL-12 的重组腺病毒载体稳定转导的人 MSCs（MSC/IL-12）的抗肿瘤活性在肾细胞癌（RCC）的小鼠异种移植模型中进行了评估。在体内研究之前，确认了腺病毒载体中转基因蛋白 IL-12 的表达和生物活性。通过将 786-0 细胞皮下注射到裸鼠中，建立了 RCC 的裸鼠模型。单次剂量将 MSC/IL-12 注入尾静脉侧。结果表明，MSC/IL-12 的全身给药减少了 786-0 RCC 的生长，并显著延长了小鼠的存活时间。这些转染细胞在静脉内注射后可以归巢到肿瘤，并大量产生局部 IL-12 蛋白。相比之下，全身的 IL-12 水平略有升高。进一步的研究表明，MSC/IL-12 的抗肿瘤活性取决于 NK 细胞和 IFN-γ在这种实验环境中的存在。这些数据表明，成体 MSC 持续产生 IL-12 具有减少 RCC 生长和增强荷瘤小鼠存活的潜力。
