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Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients
Jean Claude Reubi1, Beatrice Waser, Renzo Cescato
1Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, P.O. Box 62, Murtenstrasse 31, CH-3010 Berne, Switzerland. reubi@pathology.unibe.ch
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.
Insights
Octreotide therapy causes internalization of somatostatin receptor subtype 2 (sst(2)) in neuroendocrine tumors. This study provides the first evidence of sst(2) receptor internalization in patients, revealing insights into receptor dynamics.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Somatostatin receptor subtype 2 (sst(2)) is a key biomarker in neuroendocrine tumors (NETs), typically found on the cell membrane.
- Previous animal studies indicated that somatostatin analog treatment can induce sst(2) internalization in tumors.
Purpose of the Study:
- To investigate whether sst(2) receptors internalize in human neuroendocrine tumors following octreotide treatment.
- To compare sst(2) receptor localization in patients treated with octreotide versus untreated patients.
Main Methods:
- Analysis of neuroendocrine tumor samples from patients treated with varying octreotide doses before and during surgery.
- Immunohistochemistry using three distinct sst(2) antibodies.
- Confirmation of sst(2) expression and internalization via immunoblotting and in vitro receptor autoradiography.
Main Results:
- High-dose octreotide treatment led to predominantly internalized sst(2).
- Low-dose octreotide resulted in a mixed ratio of internalized and membranous sst(2).
- Untreated patients exclusively showed membranous sst(2); internalized receptors were found in endosomes and lysosomes.
Conclusions:
- This study presents the first evidence of sst(2) receptor internalization in human neuroendocrine tumors during octreotide therapy.
- Findings offer new insights into the biological behavior and trafficking dynamics of sst(2) receptors in patients.
- The results highlight the impact of octreotide treatment on sst(2) receptor localization in vivo.
