To develop genetically engineered bone marrow mesenchymal stem cells (BMSCs) that carries a radiotherapy gene to target triple-negative breast cancer (TNBC) and to evaluate the efficacy of radiation damage within the tumor microenvironment. The early growth response protein1 (Egr1)-human sodium iodide symporter (hNIS) gene was transfected into BMSCs by lentiviral transfection and the expression levels were evaluated by quantitative reverse transcription polymerase chain reaction. Transwell and adipogenesis and osteogenesis assays were performed to determine the targeting properties and adipogenic and osteogenic characteristics of the transgenic stem cells. The uptake of radioiodine and the efflux characteristics of the transgenic stem cells were determined by iodine uptake experiments. 131I-SPECT imaging was used to determine the characteristics of targeting to TNBC and to quantify the iodine uptake of transgenic stem cells in vivo. The effects of 131I treatment on BMSCs were characterized using tumor growth, immune cell infiltration, and tumor invasion endpoints based on immunohistochemistry and flow cytometry analysis of tumor samples. BMSCs-Egr1-hNIS cells abundantly express hNIS after radiation induction and are chemotactically attracted to TNBC tumors. Iodine uptake of BMSCs-Egr1-hNIS gradually increased with increasing induction concentrations and times. When the inductive concentration of 131I was >100 μCi/mL and lasted for 36 h, the rate of iodine uptake in cells increased. In vitro, the radioiodine quickly flowed out from cells within 20 min but in vivo, the rate of radioiodine loss was significantly slower and occurred over 24 h. After 131I therapy, tumor growth was inhibited, white blood cells infiltrated into tumor site and the levels of invasion-related cytokines significantly decreased. BMSCs-Egr1-hNIS-mediated 131I therapy can achieve precisely targeted radiotherapy to inhibit tumor growth, promote immune cell infiltration to the tumor sites, and reduce the invasiveness and metastasis characteristics of tumor cells.
Keywords: Triple-negative breast cancer; bone marrow mesenchymal stem cell; early growth response protein1; sodium iodide symporter; tumor microenvironment.