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.