2015-07-01
Novel Molecular Mechanisms of Resistance to Somatostatin Analog Treatment in Pituitary Adenomas
Publication
Publication
Nieuwe moleculaire mechanismen achter resistentie voor behandeling met somatostatine analoga bij hypofyse adenomen
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, we demonstrated that glucocorticoids are able to induce ß-arrestin-1 and repress ß-arrestin 2 expression, that this process is reversible and is antagonized by the co-incubation with a glucocorticoid-receptor antagonist. Finally, throughout the in vitro comparison between the classical and the newly available SSAs in GH- secreting adenoma cell cultures, we uncovered some unknown tumor specific properties of pasireotide (SSTR panligand), opening the way for a better understanding of the use of this compound in the clinical practice.
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L.J. Hofland (Leo) | |
Erasmus University Rotterdam | |
The studies described in this thesis were conducted at the Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center Rotterdam | |
hdl.handle.net/1765/78329 | |
Organisation | Erasmus MC: University Medical Center Rotterdam |
Gatto, F. (2015, July). Novel Molecular Mechanisms of Resistance to Somatostatin Analog Treatment in Pituitary Adenomas. Retrieved from http://hdl.handle.net/1765/78329 |