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

Abstract

UNLABELLED:

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.

CONCLUSION:

This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery.

• Authors: Kerstin Knoop, Nathalie Schwenk, Kathrin Schmohl, Andrea Müller, Christian Zach, Clemens Cyran, Janette Carlsen, Guido Böning, Peter Bartenstein, Burkhard Göke, Ernst Wagner, Peter J Nelson, Christine Spitzweg
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 56 Issue 4 Pg. 600-6 (Apr 2015) ISSN: 1535-5667 [Electronic] United States
• PMID: 25745085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Chemical References

• CCL5 protein, human
• Chemokine CCL5
• Iodine Radioisotopes
• Symporters
• sodium-iodide symporter

Topics

• Animals
• Cell Line, Tumor
• Chemokine CCL5 (metabolism)
• Colonic Neoplasms (radiotherapy)
• Female
• Fibroblasts (metabolism)
• Genetic Therapy (methods)
• Humans
• Iodine Radioisotopes (therapeutic use)
• Liver Neoplasms (radiotherapy)
• Magnetic Resonance Imaging
• Mesenchymal Stem Cells (cytology)
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Plasmids (metabolism)
• Positron-Emission Tomography
• Radionuclide Imaging
• Symporters (chemistry, genetics)
• Transgenes
• Tumor Microenvironment