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

Abstract

Context: Somatostatin receptor subtype 2 (sst₂) 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 sst₂ tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst₂. Patients and Methods: In the present study, we evaluated whether sst₂ 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. Sst₂ immunohistochemistry was performed in all samples with three different sst₂ antibodies (R2-88, UMB-1, and SS-800). Sst₂ receptor expression was confirmed by immunoblotting and in vitro receptor autoradiography. Results: Patients receiving a high dose of octreotide showed predominantly internalized sst₂, and patients with a low dose of octreotide had a variable ratio of internalized vs. membranous sst₂, whereas untreated patients had exclusively membranous sst₂. The internalized sst₂ receptor corresponded to a single sst₂ band in immunoblots and to sst₂ receptors in in vitro receptor autoradiography. Although generally found in endosome-like structures, internalized sst₂ receptors were also identified to a small extent in lysosomes, as seen in colocalization experiments. Conclusion: It is the first evidence showing that sst₂ receptors can be internalized in sst₂-expressing neuroendocrine tumors in patients under octreotide therapy, providing clues about sst₂ receptor biology and trafficking dynamics in patients.