Growth factor expression in cold and hot thyroid nodules

Hot thyroid nodules (HTNs) are predominantly caused by constitutively activ ating thyrotropin receptor (TSHR) mutations leading to an activation of the cyclic adenosine monophosphate (cAMP)-cascade that stimulates growth and f unction of thyroid epithelial cells and confers growth advantage. In contra st to HTNs, the molecular etiology of szintigraphically cold thyroid nodule s (CTNs) is largely unknown. An increased prevalence of toxic multinodular goiters in iodine-deficient regions has been reported. Growth factors incre ase during early stages of iodine deficiency in rats. These growth factors could modulate the proliferation of thyrocytes. In order to determine if an d which growth factors could modulate the increase in thyroid epithelial ce ll proliferation in late stages of CTNs and HTNs we investigated epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and TGF- beta (1) concentrations by enzyme-linked immunosorbant assay (ELISA) in CTN s (n 7), HTNs (n = 9), and their normal surrounding tissue (ST). Insulin-li ke growth factor-1 (IGF-1) was determined in CTNs (n = 5) and HTNs (n = 10) and their surrounding tissues by radioimmunoassay (RIA). We found lower co ncentrations of all investigated growth factors and iodine in CTNs compared to surrounding normal tissues (ST). Only iodine showed a significant diffe rence. Furthermore, we found significantly lower concentrations of EGF and TGF-beta (1) concentration in HTNs compared to their STs. Differences of TG F-alpha and IGF-1 were not significant. In conclusion, low EGF, TGF-cu, and IGF-1 concentrations in most CTNs in spite of low iodine concentrations ar gue against a pathophysiologic role of EGF, TGF-alpha, or IGF-1 in late sta ges of CTNs. The low EGF, TGF-alpha, and IGF-1 concentrations in HTNs irres pective of their clonal origin or the presence or absence of activating mut ations argue for increased cAMP as the primary cause for thyroid epithelial cell proliferation in established HTNs. However, the pathophysiologic sign ificance of low TGF-beta (1) concentrations in CTNs and HTNs remains to be elucidated. It might be possible that growth factors like EGF, TGF-alpha, T GF-beta (1), and IGF-1 play a more prominent role during early clonal expan sion and that aberrant intrinsic signaling through a somatic mutation (e.g. , TSHR for HTNs) confers the predominant selective growth advantage in late r stages of HTNs or CTNs.