Meseanchymal stem cell mediated sodium iodide symporter gene therapy of breast cancer
Ryan, James John
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Introduction: The Sodium Iodide Symporter (NIS) facilitates iodide accumulation in the thyroid and radioiodide imaging and treatment of thyroid disease. Studies have suggested that elevated levels of NIS expression in malignant breast tissue may facilitate diagnosis, imaging and treatment of breast cancer. Alternative approaches, such as Adenovirus-based NIS gene therapy is limited by vector immunogenicity and an inability to specifically target tumours. Mesenchymal Stem Cells (MSCs) may represent appropriate cellular vehicles as a result of their proven tumour tropism and immune privilege. The aim of this project was to determine the presence, relevance and regulation of native mammary NIS expression and to explore the potential of MSC -mediated NIS gene therapy of breast cancer. Methods: Expression of NIS, and putative regulators (Retinoic acid receptors (RAR), Estrogen receptor (ER), Phosphoinositide-3-kinase (PI3K), and Thyroid hormone receptors (THR)) were determined by Relative Quantitative-Polymerase Chain Reaction (RQ-PCR) in 100 breast tissue specimens that included 15 controls. In vitro the effects of individual and combined estradiol, retinoic acid (RA) and thyroxine stimulation on NIS expression was determined in breast cancer cell lines. MSCs were engineered to express NIS and characterised in terms of phenotype and persistence of NIS expression and function. The distribution of systemically injected MSC-NIS in non-invasive disease and labelled MSCs in metastatic murine breast cancer models was determined over time. Results: NIS gene expression levels were significantly higher in malignant tissue compared to normal but even higher in benign tissue. Significant positive correlations in gene expression suggested relationships between NIS and putative regulators: RAR[alpha], RAR[beta], ER[alpha] and THR[beta] which were confirmed by estradiol, RA and thyroxine stimulation of NIS expression in vitro. Combined stimulation with RA and thyroxine had a synergistic effect on NIS expression. MSCs were successfully engineered to express NIS with no significant impact on phenotype observed. A cytotoxic effect on adjacent breast cancer cells was also demonstrated using Iodide131 in vitro. In animal models, initial ectopic engraftment was shown to deplete over time except in malignant tissue and tumour-targeted MSC tropism as well as successful delivery of transgene to tumour sites was observed. Conclusion: This thesis presents novel data on the presence and relevance of mammary NIS expression in human tissues. It also supports a regulatory role for estradiol and retinoic acid, and introduces the potential for thyroid hormones to stimulate mammary NIS expression. The phenotype and migratory behaviour of labelled and Ad5/CMV/NIS infected MSCs demonstrated here strongly support the potential of MSC-mediated NIS gene therapy of breast cancer
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