title: Stromal targeting of sodium iodide symporter using mesenchymal stem cells allows enhanced imaging and therapy of hepatocellular carcinoma.
abstract: 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.
authors: Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
authors: Kerstin
authors: K
authors: Knoop
authors: Nathalie
authors: N
authors: Schwenk
authors: Patrick
authors: P
authors: Dolp
authors: Michael J
authors: MJ
authors: Willhauck
authors: Christoph
authors: C
authors: Zischek
authors: Christian
authors: C
authors: Zach
authors: Markus
authors: M
authors: Hacker
authors: Burkhard
authors: B
authors: Göke
authors: Ernst
authors: E
authors: Wagner
authors: Peter J
authors: PJ
authors: Nelson
authors: Christine
authors: C
authors: Spitzweg
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000628:therapy*; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000235:genetics; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters
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