Mesenchymal Stem Cell–Mediated, Tumor Stroma–Targeted Radioiodine Therapy of Metastatic Colon Cancer Using the Sodium Iodide Symporter as Theranostic Gene

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.

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

“…MSCs spontaneously migrate to damaged tissue and are actively recruited to solid tumors (154). MSCs can be engineered to express NIS to selectively deliver radionuclides for better visualization and effective treatment of metastases.…”

“…Indeed, NIS has been successfully used to detect and treat colorectal cancer metastases in rat liver in a model involving colorectal carcinoma LS174t cells injected into nude mice. When NIS-expressing MSCs were injected systemically into this model, 131 I − -treated mice displayed a 40% reduction in liver metastases when compared to control mice (154). …”

Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System

“…128 MSCs have also been shown to be useful for the delivery of therapeutic genes in a colon cancer liver metastasis mouse model. 129 There are many other examples of MSCs being a potential vehicle for therapeutic delivery to tumors, including to brain tumors, 130 lung tumors, 131 hepatocellular carcinoma, 132 and prostate cancer. 133 These studies describe the use of MSCs for delivering not only therapeutic genes, but also therapeutic drugs and theranostic agents.…”

Stem Cell-Based Therapies for Cancer

“…The short half-life and poor bioavailability of cancer-specific drugs are the key players that contribute to failure of current therapies. Recently, numerous studies have demonstrated the unique inherent tumor-tropic properties of stem cells including but not limited to mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) ( Jones, Lamb, Goldman, & Di Stasi, 2014;Knoop et al, 2015;Singh, Kalsan, Kumar, Saini, & Chandra, 2015;Stuckey and Shah, 2014). In addition, adult stem cells in their unmodified state have antitumor effects owing to factors that are released and physical interactions that are established between the stem cell and the tumor cell (Schichor et al, 2012).…”