Radio-Iodide Treatment: From Molecular Aspects to the Clinical View

Abstract

Thyroid radio-iodide therapy (RAI) is one of the oldest known and used targeted therapies. In thyroid cancer, it has been used for more than eight decades and is still being used to improve thyroid tumor treatment to eliminate remnants after thyroid surgery, and tumor metastases. Knowledge at the molecular level of the genes/proteins involved in the process has led to improvements in therapy, both from the point of view of when, how much, and how to use the therapy according to tumor type. The effectiveness of this therapy has spread into other types of targeted therapies, and this has made sodium/iodide symporter (NIS) one of the favorite theragnostic tools. Here we focus on describing the molecular mechanisms involved in radio-iodide therapy and how the alteration of these mechanisms in thyroid tumor progression affects the diagnosis and results of therapy in the clinic. We analyze basic questions when facing treatment, such as: (1) how the incorporation of radioiodine in normal, tumor, and metastatic thyroid cells occurs and how it is regulated; (2) the pros and cons of thyroid hormonal deprivation vs. recombinant human Thyroid Stimulating Hormone (rhTSH) in radioiodine residence time, treatment efficacy, thyroglobulin levels and organification, and its influence on diagnostic imaging tests and metastasis treatment; and (3) the effect of stunning and the possible causes. We discuss the possible incorporation of massive sequencing data into clinical practice, and we conclude with a socioeconomical and clinical vision of the above aspects.

Keywords: adjuvant therapy; differentiated thyroid cancer; radio-iodide treatment; radio-iodine-refractory thyroid cancer; recombinant human TSH; sodium/iodide symporter (NIS); stunning; theragnostic; thyroid cancer; thyroid hormonal deprivation.

Figure 1

Putative effects of radio-iodide in the cell. Two types of effects can be experienced: direct and indirect. Four main types of damage can occur as a result of direct effects: (1) direct DNA damage such as single-strand and double-strand breaks, (2) increased ROS, (3) inactivation of DNA repair proteins to compensate for elevated ROS, (4) elevated ROS-mediated protein inactivation of proteins directly implicated in iodide transport, such as NIS, or in general thyroid differentiation (TPO, Tg, Duox2, TSH-R, Pendrin, etc.). Indirect non-targeted effects of radiation (5) occur in the surrounding cells as a result of bystander and abscopal effects. In any case, damage intensity would depend on radioiodine concentration and subcellular localization. Abbreviations: NIS: sodium/iodide symporter; TPO: thyroid peroxidase; Tg: thyroglobulin; TSH-R: Thyroid Stimulating Hormone receptor; ROS: reactive oxygen species; Duox2: Dual oxidase 2; MCT8: Monocarboxylate transporter 8.

Figure 2

Schematic representation of the biosynthesis of thyroid hormones (TH) in normal and differentiated thyroid cancer (DTC) thyroid tissue. (a) Physiology of a thyroid cell. The thyroid follicle is made up of epithelial cells. The basolateral membrane is in contact with the blood stream, where iodide from the diet, or iodide recycled from dehalogenation in peripheral tissues, arrives. Iodide is transported against its concentration gradient by the plasma membrane protein sodium/iodide symporter (NIS) (red diamonds) thanks to the sodium gradient provided by the sodium and potassium-ATPase. NIS can concentrate more than 40–100 times the concentration of iodide in the blood. The iodide goes to the apical membrane side of the cell, essentially by concentration gradient, and is then transported to the colloid by means of different transporters (Anoctamin 1 (Ano1/TMEM16A), Pendrin and cystic fibrosis transmembrane conductance regulator (CFTR) located in the apical membrane of the thyroid follicle cell. The Duox2 enzyme generates H₂O₂, which is used by TPO to oxidize iodide in the TG molecule (organification), forming iodotyrosine residues (MIT and DIT). TPO itself couples two residues of MIT and/or DIT to synthetize the thyroid hormones (TH) T3 and T4, although they are still bound to TG. Iodinated TG (TG-I), as iodotyrosine or iodotyronine residues, accumulates in the colloid until there is further need for TH. When TH is required, TG is internalized into the cytoplasm, proteolyzed, and the iodinated residues are released. The iodine from the MIT and DIT residues is recycled by the Iodotyrosine dehalogenase 1 (DEHAL) enzyme. T3 and T4 are transported to the bloodstream by the MCT8 membrane protein. TSH, through its receptor on the basolateral membrane (TSH-R), is the master hormone that regulates most of the indicated processes at different levels, in addition to cell proliferation and growth. Immunohistochemistry shows the expression of NIS in the basolateral membrane of a non-anaplastic thyroid. (b) Thyroid tumor cell physiology in differentiated thyroid cancer (DTC). In tumor cells, the follicular structure is not always well preserved, and TG can be released into the bloodstream. The expression of key TH synthesis proteins is reduced (TSH-R, NIS, TPO, and pendrin) or delocalized from the place where they are functional, which prevents correct TH synthesis. Furthermore, Duox2 is usually not diminished, so the production of H₂O₂ does not decrease, which may lead to an increase in ROS that alter the synthesis and degradation of cell mechanisms. Immunohistochemistry shows the expression of NIS localized both at the basolateral membrane and in the cytoplasm in DTC tissue.

Figure 3

Schematic representation of Radioactive Iodide (RAI) therapy in patients with differentiated thyroid cancer (DTC). After tumor diagnosis, the final goal of both pre-RAI treatments is to achieve maximum radioiodine accumulation in tumor cells, with maximum residence time during ¹³¹I therapy. Molecularly speaking, this translates to the maximum accumulation of radioiodine through NIS and the maximum iodine organification in TG or other molecules that are able to oxidize iodide. Abbreviations: TH: Thyroid Hormones; TG: thyroglobulin; TSH: Thyroid Stimulating Hormone; rhTSH: recombinant human TSH; MRI: Magnetic resonance imaging; SPECT: Single-photon emission computed tomography; PET: Positron emission tomography.