Novel targets for thyroid cancer treatment
The sodium iodide symporter (NIS) is an intrinsic plasma membrane glycoprotein that mediates the active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular lactating mammary gland. In addition to its key function in thyroid physiology, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as therapeutic radioiodine application in benign and malignant thyroid disease. Functional NIS expression in differentiated thyroid carcinomas allows not only postoperative localization and ablation of the thyroid remnant as well metastases, but also provides the possibility of postablative 131I total body scanning that can diagnose local and metastatic residual and recurrent disease followed by 131I ablation. Thyroidal NIS expression therefore provides the molecular basis for the most effective form of systemic anticancer radiotherapy available to the clinician today, as long as the degree of tumor cell differentiation provides a sufficient level of endogenous NIS expression. In dedifferentiated thyroid tumors different approaches for reinduction of functional NIS expression have been investigated, including redifferentiation by retinoids and thiazolidinediones, as well as epigenetic modification by histone deacetylase inhibition or demethylation. Furthermore, cloning and characterization of the NIS gene has paved the way for the development of a novel cytoreductive gene therapy strategy based on targeted NIS expression in thyroidal and nonthyroidal cancer cells followed by therapeutic application of 131I or alternative radionuclides, including 188Re and 211At. In addition, the possibility of direct and non-invasive imaging of functional NIS expression by 123I- and 99mTc-scintigraphy or 124I-PET-imaging allows the application of NIS as a novel reporter gene. In conclusion, NIS represents one of the oldest and most successful targets for molecular imaging and targeted radionuclide therapy. Its dual role as reporter and therapy gene opens promising perspectives for diagnostic and therapeutic application of NIS in cancer treatment in and outside the thyroid gland.