Internalized Somatostatin Receptor Subtype 2 in Neuroendocrine Tumors of Octreotide-Treated Patients

摘要

Context: Somatostatin receptor subtype 2 (sst_(2)) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst_(2) tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst_(2).Patients and Methods: In the present study, we evaluated whether sst_(2) expressed in neuroendocrine tumors of patients treated with octreotide are also internalized. Tumor samples were assessed in patients that were treated with various octreotide modalities before and during surgery and compared with tumor samples from untreated patients. Sst_(2) immunohistochemistry was performed in all samples with three different sst_(2) antibodies (R2-88, UMB-1, and SS-800). Sst_(2) receptor expression was confirmed by immunoblotting and in vitro receptor autoradiography.Results: Patients receiving a high dose of octreotide showed predominantly internalized sst_(2), and patients with a low dose of octreotide had a variable ratio of internalized vs. membranous sst_(2), whereas untreated patients had exclusively membranous sst_(2). The internalized sst_(2) receptor corresponded to a single sst_(2) band in immunoblots and to sst_(2) receptors in in vitro receptor autoradiography. Although generally found in endosome-like structures, internalized sst_(2) receptors were also identified to a small extent in lysosomes, as seen in colocalization experiments.Conclusion: It is the first evidence showing that sst_(2) receptors can be internalized in sst_(2)-expressing neuroendocrine tumors in patients under octreotide therapy, providing clues about sst_(2) receptor biology and trafficking dynamics in patients.