Thyroid hormone (TH) is a pleiotropic agent that has widespread
biological functions, i.e., it controls cellular growth, tissue development and homeostasis and neoplastic transformation. Suitable TH levels are critical for the development of various types of tissues and are essential for the regulation of metabolic processes throughout life. The serum concentrations of TH affect its
biological activity. Moreover, at tissue level, TH action is regulated by the expression and activity of deiodinases, i.e., the
enzymes that mediate the metabolic pathways by activating and/or inactivating TH. The type I and II deiodinases (D1 and D2) initiate TH action by converting
thyroxine (T4) into the active TH form (T3), whereas
type III deiodinase (D3) mediates the local attenuation of TH by converting T4 and T3 into the inactive metabolites rT3 and T2, respectively. The
deiodinase system is a potent mechanism of pre-receptoral control of TH action; it is often altered in such pathological conditions as
cancer. D3 is widely expressed in embryonic tissues and in placenta, where it blocks excessive maternal-to-fetal transfer of TH. In contrast, during late neonatal and adult life, D3 is expressed mainly in the central nervous system and skin. Interestingly, D3 expression is re-activated in various types of human
cancers. Here we review recent evidence that D3 expression plays a crucial role in human
carcinogenesis, and speculate as to its complex role in the regulation of cell proliferation in several neoplastic contexts. It is conceivable that the local modulation of TH action via deiodinases is a powerful molecular tool to manipulate the intracellular TH status, thus influencing the growth and maintenance of selected
hormone-dependent
cancers.