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J Nucl Med. 2015 Apr;56(4):600-6. doi: 10.2967/jnumed.114.146662. Epub 2015 Mar 5.

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

Author information

1
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
2
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
3
Department of Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University, Munich, Germany.
4
Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Munich, Germany; and.
5
Clinical Biochemistry Group, Department of Internal Medicine and Policlinic IV, Ludwig-Maximilians-University, Munich, Germany.
6
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany Christine.Spitzweg@med.uni-muenchen.de.

Abstract

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.

KEYWORDS:

RANTES; colon cancer; gene therapy; hepatic metastases; mesenchymal stem cells; sodium iodide symporter

PMID:
25745085
DOI:
10.2967/jnumed.114.146662
[Indexed for MEDLINE]
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