Radioactive Iodine-Refractory Differentiated Thyroid Cancer and Redifferentiation Therapy

Abstract

The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.

Keywords: Isotopes; Sodium-iodide symporter; Thyroid neoplasms.

Fig. 1. Regulation of the sodium iodide symporter (NIS) upstream enhancer (NUE) at the transcriptional level in thyroid cells. TSHR, thyroid stimulating hormone receptor; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CRE, cAMP-response element; CREM, CRE-modulator; Ref1, apurinic apyrimidinic endonuclease redox effector factor-1; Pax8, paired box gene-8; TGFβ, transforming growth factor β; TLR4, Toll-like receptor 4; NF-κB, p65, a member of the class II nuclear factor κ-light-chain-enhancer of activated B cells, p65; PTTG1, pituitary tumor-transforming gene-1; PBF, PTTG1-binding factor.

Fig. 2. Known pathways involved in the regulation of sodium iodide symporter (NIS) in thyroid cancer. RTK, receptor tyrosine kinase; IGF-1, insulin-like growth factor-1; TGFβ, transforming growth factor β; PTC, papillary thyroid cancer; PI3K, phosphoinositide 3-kinase; RasGRP3, Ras guanyl releasing protein 3; PAX8, paired box gene-8; MEK, mitogen-activated extracellular signal-regulated kinase; ERK, extracellular regulated protein kinase; mTOR, mechanistic target of rapamycin; VEGFA, vascular endothelial growth factor A; MET, mesenchymal to epithelial transition factor; TSP1, thrombospondin 1; TIMP3, tissue inhibitor of metalloproteinases 3.