Knoop Kerstin, Schwenk Nathalie, Schmohl Kathrin, Müller Andrea, Zach Christian, Cyran Clemens, Carlsen Janette, Böning Guido, Bartenstein Peter, Göke Burkhard, Wagner Ernst, Nelson Peter J, Spitzweg Christine
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
J Nucl Med. 2015 Apr;56(4):600-6. doi: 10.2967/jnumed.114.146662. Epub 2015 Mar 5.
The tumor-homing property of mesenchymal stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter (NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. We have previously shown that linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease.
To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. RANTES-NIS-MSCs were injected intravenously, followed by (123)I scintigraphy, (124)I PET imaging, and (131)I therapy.
Results show robust MSC recruitment with RANTES/CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of (131)I in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved overall survival.
This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery.
间充质干细胞（MSC）的肿瘤归巢特性可实现治疗性基因向肿瘤微环境的靶向递送。将碘化钠同向转运体（NIS）用作治疗诊断基因，可在应用治疗性放射性碘之前对MSC的生物分布和转基因表达进行无创成像。我们之前已经表明，将治疗性转基因表达与趋化因子CCL5/调节激活正常T细胞表达和分泌因子（RANTES）的诱导相联系，可使原发性肿瘤内的表达更具针对性，因为过继转移的MSC会发展出癌相关成纤维细胞样特征。尽管RANTES/CCL5-NIS靶向在原发性肿瘤治疗中已显示出疗效，但尚不清楚其在控制转移性疾病生长方面是否也有效。
为了扩大肿瘤靶点的潜在范围，我们在通过脾内注射人结肠癌细胞系LS174t建立的结肠癌肝转移小鼠模型中，研究了在RANTES/CCL5启动子（RANTES-NIS-MSC）控制下转染NIS的MSC的生物分布和肿瘤募集情况。静脉注射RANTES-NIS-MSC，随后进行（123）I闪烁扫描、（124）I正电子发射断层扫描（PET）成像和（131）I治疗。
结果显示，通过肿瘤选择性碘摄取、免疫组织化学和实时聚合酶链反应证明，RANTES/CCL5启动子激活可使肝转移瘤基质内的MSC大量募集。在RANTES-NIS-MSC治疗的小鼠中应用（131）I进行治疗，导致肿瘤生长显著延迟，总生存期延长。
这种新型基因治疗方法为MSC介导的基因递送后NIS介导的转移性癌症放射性核素治疗开辟了前景。
