Stromal Targeting of Sodium Iodide Symporter Using Mesenchymal Stem Cells Allows Enhanced Imaging and Therapy of Hepatocellular Carcinoma
| Autor: | Nathalie Schwenk, Burkhard Göke, Christine Spitzweg, Kerstin Knoop, Ernst Wagner, Christoph Zischek, Michael J. Willhauck, Peter J. Nelson, Markus Hacker, Patrick Dolp, Christian Zach |
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| Rok vydání: | 2013 |
| Předmět: |
Sodium-iodide symporter
Chemokine Carcinoma Hepatocellular Stromal cell Transgene Cell- and Tissue-Based Therapy Gene Expression CCL5 Iodine Radioisotopes Mice Cell Line Tumor Genetics Animals Humans Tissue Distribution RNA Messenger Molecular Biology Research Articles Symporters biology Liver Neoplasms Mesenchymal stem cell Gene Transfer Techniques Mesenchymal Stem Cells Xenograft Model Antitumor Assays Molecular biology Disease Models Animal Cell culture Positron-Emission Tomography Symporter Cancer research biology.protein Molecular Medicine Female |
| Zdroj: | Human Gene Therapy. 24:306-316 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2012.104 |
| Popis: | The tumor-homing property of mesenchymal stem cells (MSC) has lead to their use as delivery vehicles for therapeutic genes. The application of the sodium iodide symporter (NIS) as therapy gene allows noninvasive imaging of functional transgene expression by (123)I-scintigraphy or PET-imaging, as well as therapeutic application of (131)I or (188)Re. Based on the critical role of the chemokine RANTES (regulated on activation, normal T-cell expressed and presumably secreted)/CCL5 secreted by MSCs in the course of tumor stroma recruitment, use of the RANTES/CCL5 promoter should allow tumor stroma-targeted expression of NIS after MSC-mediated delivery. Using a human hepatocellular cancer (HCC) xenograft mouse model (Huh7), we investigated distribution and tumor recruitment of RANTES-NIS-engineered MSCs after systemic injection by gamma camera imaging. (123)I-scintigraphy revealed active MSC recruitment and CCL5 promoter activation in the tumor stroma of Huh7 xenografts (6.5% ID/g (123)I, biological half-life: 3.7 hr, tumor-absorbed dose: 44.3 mGy/MBq). In comparison, 7% ID/g (188)Re was accumulated in tumors with a biological half-life of 4.1 hr (tumor-absorbed dose: 128.7 mGy/MBq). Administration of a therapeutic dose of (131)I or (188)Re (55.5 MBq) in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved survival without significant differences between (131)I and (188)Re. These data demonstrate successful stromal targeting of NIS in HCC tumors by selective recruitment of NIS-expressing MSCs and by use of the RANTES/CCL5 promoter. The resulting tumor-selective radionuclide accumulation was high enough for a therapeutic effect of (131)I and (188)Re opening the exciting prospect of NIS-mediated radionuclide therapy of metastatic cancer using genetically engineered MSCs as gene delivery vehicles. |
| Databáze: | OpenAIRE |
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