Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients.
BACKGROUND
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).


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.


CONCLUSIONS
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.
Division 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
Jean Claude
JC
Reubi
Beatrice
B
Waser
Renzo
R
Cescato
Beat
B
Gloor
Christoph
C
Stettler
Emanuel
E
Christ
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001345:Autoradiography; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007457:Iodine Radioisotopes; D007668:Kidney; D008247:Lysosomes / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015282:Octreotide / Q000627:therapeutic use*; D017481:Receptors, Somatostatin / Q000276:immunology / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D007457:Iodine Radioisotopes; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2; D015282:Octreotide