Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Mol Ther. 2011 Sep;19(9):1704-13. doi: 10.1038/mt.2011.93. Epub 2011 May 17.
Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows noninvasive imaging of functional NIS expression by (123)I-scintigraphy or (124)I-PET imaging before the application of a therapeutic dose of (131)I. NIS expression provides a novel mechanism for the evaluation of mesenchymal stem cells (MSCs) as gene delivery vehicles for tumor therapy. In the current study, we stably transfected bone marrow-derived CD34(-) MSCs with NIS cDNA (NIS-MSC), which revealed high levels of functional NIS protein expression. In mixed populations of NIS-MSCs and hepatocellular cancer (HCC) cells, clonogenic assays showed a 55% reduction of HCC cell survival after (131)I application. We then investigated body distribution of NIS-MSCs by (123)I-scintigraphy and (124)I-PET imaging following intravenous (i.v.) injection of NIS-MSCs in a HCC xenograft mouse model demonstrating active MSC recruitment into the tumor stroma which was confirmed by immunohistochemistry and ex vivo γ-counter analysis. Three cycles of systemic MSC-mediated NIS gene delivery followed by (131)I application resulted in a significant delay in tumor growth. Our results demonstrate tumor-specific accumulation and therapeutic efficacy of radioiodine after MSC-mediated NIS gene delivery in HCC tumors, opening the prospect of NIS-mediated radionuclide therapy of metastatic cancer using MSCs as gene delivery vehicles.
由于其作为报告基因和治疗基因的双重作用，钠碘转运体 (NIS) 允许在应用治疗剂量的 (131)I 之前，通过 (123)I 闪烁显像或 (124)I-PET 成像对功能性 NIS 表达进行非侵入性成像。NIS 表达为评价间充质干细胞 (MSCs) 作为肿瘤治疗基因传递载体提供了一种新的机制。在当前的研究中，我们通过 NIS cDNA (NIS-MSC) 稳定转染骨髓来源的 CD34(-)MSCs，发现其具有高水平的功能性 NIS 蛋白表达。在 NIS-MSC 和肝癌 (HCC) 细胞的混合群体中，克隆形成试验显示，在应用 (131)I 后 HCC 细胞的存活率降低了 55%。然后，我们通过静脉内 (i.v.) 注射 NIS-MSC 在 HCC 异种移植小鼠模型中进行 (123)I 闪烁显像和 (124)I-PET 成像，研究了 NIS-MSC 的体内分布，结果显示 NIS-MSC 积极募集到肿瘤基质中，免疫组织化学和离体 γ 计数器分析证实了这一点。三周期系统 MSC 介导的 NIS 基因传递后应用 (131)I，导致肿瘤生长明显延迟。我们的研究结果表明，在 HCC 肿瘤中，MSC 介导的 NIS 基因传递后放射性碘具有肿瘤特异性积累和治疗效果，为使用 MSCs 作为基因传递载体的转移性癌症的 NIS 介导放射性核素治疗开辟了前景。
