Abstract
Insulinomas constitute a subgroup of pancreatic endocrine tumors showing B cell differentiation and clinical symptoms related to inappropriate insulin secretion (WHO). Many endocrine tumors express somatostatin receptors (sstrs), which can be visualized by octreotide scintigraphy; however, about half of all insulinomas are reported to be negative. Previous immunohistochemical investigations with antibodies to sstr subtypes 1, 2, 3, and 5 have revealed differences in expression between various neuroendocrine tumors. In the present study, the immunoreactivity to all five human sstr was studied in ten benign and six malignant human insulinomas. Sstr4 was the receptor subtype most frequently expressed in both benign and malignant tumors. A difference in the immunohistochemical sstr5 expression pattern was seen between benign and malignant tumors: Three of the six malignant tumors, but none of the benign tumors, expressed sstr5. The other receptor subtypes were expressed in low numbers with no difference between benign and malignant tumors. The finding of a strong expression of sstr4 in both benign and malignant insulinomas suggests that this receptor subtype could be of importance for diagnostic and therapeutic use.
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Brazeau P, Vale W, Burgus R, Guillemin R. Isolation of somatostatin (a somatotropin release inhibiting factor) of ovine hypothalamic origin. Can J Biochem 52:1067–72, 1974.
Yamada Y, Post SR, Wang K, Tager HS, Bell GI, Seino, S. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci U S A 89:251–5, 1992.
Yamada Y, Reisine T, Law SF, Ihara Y, Kubota A, Kagimoto S, et al. Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase. Mol Endocrinol 6:2136–42, 1992.
Yamada Y, Kagimoto S, Kubota A, Yasuda, K, Masuda K, Someya Y, et al. Cloning, functional expression and pharmacological characterization of a fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype. Biochem Biophys Res Commun 195:844–52, 1993.
Buscail L, Delesque N, Estève JP, Saint-Laurent N, Prats H, Clerc P, et al. Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes sstR1 and sstR2. Proc Natl Acad Sci U S A 91:2315–9, 1994.
Buscail L, Estève JP, Saint-Laurent N, Bertrand V, Reisine T, O’Carroll A, et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes sstr2 and sstr5 through different mechanisms. Proc Natl Acad Sci U S A 92:1580–4, 1995.
Sharma K, Patel YC, Srikant CB. Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol 10:1688–96, 1996.
Teijeiro R, Rios R, Costoya JA, Castro R, Bello JL, Devesa J, et al. Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53. Cell Physiol Biochem 12:31–8, 2002.
Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 20:157–98, 1999.
Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 146:707–16, 2002.
Solcia E, Klöppel G, Sobin LH, Capella C, DeLellis RA, Heitz PU, et al. Histological typing of endocrine tumors. 2nd ed. WHO international histological classification of tumours. Berlin: Springer; 2000.
Janson ET, Öberg K. Neuroendocrine tumors—somatostatin receptor expression and somatostatin analog treatment. Cancer Chemother Biol Response Modif Annu 21:535–46, 2003.
de Herder WW, Kwekkeboom DJ, Valkema R, Feelders RA, van Aken MO, Lamberts SW, et al. Neuroendocrine tumors and somatostatin: imaging techniques. J Endocrinol Investig 28 (11 suppl):132–6, 2005.
Vezzosi D, Bennet A, Rochaix P, Courbon F, Selves J, Pradere B, et al. Octreotide in insulinoma patients: efficacy on hypoglycaemia, relationship with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies. Eur J Endocrinol 152:757–67, 2005.
Schillaci O, Massa R, Scopinaro F. 111In-pentrotide scintigraphy in the detection of insulinomas: importance of SPECT imaging. J Nucl Med 41:459–62, 2000.
Slooter GD, Mearadji A, Breeman WA, Marquet RL, de Jong M, Krenning EP, et al. Somatostatin receptor imaging, therapy and new strategies in patients with neuroendocrine tumours. Br J Surg 88:31–40, 2001.
Portela-Gomes GM, Stridsberg M, Grimelius L, Öberg K, Janson ET. Expression of the five different somatostatin receptor subtypes in endocrine cells of the pancreas. Appl Immunohistochem Mol Morphol 8:126–32, 2000.
Reubi JC, Kvols LK, Waser B, Nagorney DM, Heitz PU, Charboneau JW, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 50:5969–77, 1990.
Reubi JC, Schaer JC, Waser B, Mengod G. Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res 54:3455–345, 1994.
Kubota A, Yamada Y, Kagimoto S, Shimatsu A, Imamura M, Tsuda K, et al. Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. J Clin Invest 93:1321–5, 1994.
Jaïs P, Terris B, Ruszniewski P, Leromancer M, Reyl-desmars F, Vissuzaine C, et al. Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours. Eur J Clin Invest 27:639–44, 1997.
de Sá SV, Corera-Giannella ML, Machado MC, de Souza JJS, Pereira MAA, Patzina RA, et al. Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas. Endocr Relat Cancer 13:69–78, 2006.
Janson ET, Stridsberg M, Gobl A, Westlin JE, Oberg K. Determination of somatostatin receptor subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies. Cancer Res 58:2375–8, 1998.
Hofland LJ, De Herder WW, Visser-Wisselaar HA, van Uffelen C, Waaijers M, Zuyderwijk J, et al. Dissociation between the effects of somatostatin (SS) and octapeptide SS-analogs on hormone release in a small subgroup of pituitary- and islet cell tumors. J Clin Endocrinol Metab 82:3011–8, 1997.
Reubi JC, Kappeler A, Waser B, Laissue J, William Hipkin R, Schonbrunn A. Immunohistochemical localization of somatostatin receptors sst2A in human tumors. Am J Pathol 153:233–45, 1998.
Kulaksiz H, Eissele R, Rossler D, Schulz S, Höllt V, Cetin Y, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut 50:52–60, 2002.
Papotti M, Bongiovanni M, Volante M, Allìa E, Landolfi S, Helboe L, et al. Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Archiv 440:461–75, 2002.
Oda Y, Tanaka Y, Naruse T, Sasanabe R, Tsubamoto M, Funahashi H. Expression of somatostatin receptor and effects of somatostatin analog on pancreatic endocrine tumors. Surg Today 32:690–4, 2002.
Bertherat J, Tenenbaum F, Perlemoine K, Videau C, Alberini JL, Richard B, et al. Somatostatin receptors 2 and 5 are the major somatostatin receptors in insulinomas: an in vivo and in vitro study. J Clin Endocrinol Metab 88:5353–6, 2003.
Hsu SM, Raine T, Fanger H. Use of avidin–biotin–peroxidase complex (ABC) in immmunoperoxidase techniques: a comparison between ABC and unlabeled (PAP) procedures. J Histochem Cytochem 29:577–80, 1981.
Fjällskog ML, Ludvigsen E, Stridsberg M, Oberg K, Eriksson B, Janson ET. Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors. Med Oncol 20:59–67, 2003.
Welin SV, Janson ET, Sundin A, Stridsberg M, Lavenius E, Granberg D, et al. High-dose treatment with a long-acting somatostatin analogue in patients with advanced midgut carcinoid tumours. Eur J Endocrinol 151:107–12, 2004.
Orlefors H, Sundin A, Ahlstrom H, Bjurling P, Bergstrom M, Lilja A, et al. Positron emission tomography with 5-hydroxytryptophan in neuroendocrine tumors. J Clin Oncol 16:2534–41, 1998.
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This work was accorded grants from the Swedish Cancer Society, the Lions Cancer Foundation at Uppsala University Hospital, and Selanders Foundation.
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Portela-Gomes, G.M., Stridsberg, M., Grimelius, L. et al. Differential Expression of the Five Somatostatin Receptor Subtypes in Human Benign and Malignant Insulinomas – Predominance of Receptor Subtype 4. Endocr Pathol 18, 79–85 (2007). https://doi.org/10.1007/s12022-007-0014-8
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DOI: https://doi.org/10.1007/s12022-007-0014-8