Mesenchymal stem cell-mediated, tumor stroma-targeted radioiodine therapy of metastatic colon cancer using the sodium iodide symporter as theranostic gene.
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.


METHODS
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
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.


CONCLUSIONS
This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery.
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Kerstin
K
Knoop
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Nathalie
N
Schwenk
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Kathrin
K
Schmohl
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Andrea
A
Müller
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
Christian
C
Zach
Department of Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University, Munich, Germany.
Clemens
C
Cyran
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
Janette
J
Carlsen
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
Guido
G
Böning
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
Peter
P
Bartenstein
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Burkhard
B
Göke
Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Munich, Germany; and.
Ernst
E
Wagner
Clinical Biochemistry Group, Department of Internal Medicine and Policlinic IV, Ludwig-Maximilians-University, Munich, Germany.
Peter J
PJ
Nelson
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany Christine.Spitzweg@med.uni-muenchen.de.
Christine
C
Spitzweg
D000818:Animals; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000532:radiotherapy; D008279:Magnetic Resonance Imaging; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D049268:Positron-Emission Tomography; D011877:Radionuclide Imaging; D027981:Symporters / Q000737:chemistry* / Q000235:genetics*; D019076:Transgenes; D059016:Tumor Microenvironment; D000099209:Sodium-Iodide Symporters
D018946:Chemokine CCL5; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C483024:CCL5 protein, human
RANTES; colon cancer; gene therapy; hepatic metastases; mesenchymal stem cells; sodium iodide symporter