Novel Molecular Mechanisms of Resistance to Somatostatin Analog Treatment in Pituitary Adenomas

markdownabstract__Abstract__ In this thesis we confirmed the pivotal role of somatostatin receptor (SSTR) subtype 2 (sst2) receptor expression in driving the biochemical responsiveness to “classical” somatostatin analog (SSA) treatment in GH-secreting adenomas. Moreover, since the variable expression of SSTRs in pituitary adenomas has been proposed as another factor affecting SSA efficacy, we showed that sst2 and sst5 are co-expressed in TSH-secreting adenomas. Differently from GH-secreting adenomas, TSHoma patients with high tumor sst5/sst2 mRNA ratio showed a good biochemical response to long-term SSA treatment. This difference between TSH- and GH-secreting adenomas points out the concept of cell type specificity. Furthermore, for the first time, we characterized the expression of GRK2 and, in particular, of ß-arrestins in different pituitary adenoma histotypes. Indeed, these molecules have been highlighted to play a pivotal role in the SSTR desensitization and trafficking processes. We highlighted the important role of these molecules as determinants of tumor responsiveness to SSA treatment in GH-secreting adenomas, both in vitro and in vivo. As far as ACTH-secreting adenomas, by use of the AtT20 cell line, w