Role of the mTOR pathway in normal and tumoral adrenal cells.

The mammalian target of rapamycin (mTOR) is a kinase of the phosphoinositide 3-kinase (PI3Ks)/protein kinase B (PKB or AKT) signaling pathway, which is one of the most important intracellular mediators of the activity of growth factors receptors, including vascular endothelial growth factor (VEGF) and insulin-like growth factors (IGFs). Dysregulation of the mTOR pathway has been found in many human tumors. Therefore, the mTOR pathway is considered as a target for antineoplastic therapy in several malignancies. Presently, the role and functions of mTOR and its signaling pathway in the normal and pathological adrenal gland has not been clarified yet. However, many growth factors and growth factor receptors, which are considered to play a role in the pathogenesis of adrenal tumors, can at least in part exert their effects through the activation of PI3K/AKT/mTOR pathway. Dysregulation of AKT has been reported in adrenocortical carcinomas and adrenomedullary tumors, named pheochromocytomas. Adrenocortical carcinomas and malignant pheochromocytomas are aggressive tumors with poor prognosis and scant treatment options. Therefore, new treatment options are warranted for these malignancies. On the basis of the current knowledge, mTOR could play a role in the pathogenesis of both adrenocortical carcinomas and pheochromocytomas. Moreover, mTOR inhibitors, interfering with the activation of several mitogenic and angiogenic factors, could be considered as a novel treatment opportunity for the management of malignant adrenal tumors.