Differential Expression of Somatostatin Receptor Subtype 1–5 Proteins in Numerous Human Normal Tissues

N. Unger; B. Ueberberg; S. Schulz; W. Saeger; K. Mann; S. Petersenn

doi:10.1055/s-0032-1314859

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2012; 120(08): 482-489
DOI: 10.1055/s-0032-1314859

Article

Differential Expression of Somatostatin Receptor Subtype 1–5 Proteins in Numerous Human Normal Tissues

N. Unger

¹Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany

,

B. Ueberberg

¹Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany

,

S. Schulz

²Institute of Pharmacology and Toxicology, University of Jena, Jena, Germany

,

W. Saeger

³Institute of Pathology, Marienhospital, Hamburg, Germany

,

K. Mann

¹Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany

,

S. Petersenn^*

¹Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany

› Author Affiliations

Abstract

5 human somatostatin receptor subtypes (sst1–5) mediate the antisecretory and antiproliferative effects of somatostatin.

We examined somatostatin receptor protein expression in 28 human normal tissues. Immunostaining was performed with specific polyclonal antibodies for sst1–5. Staining pattern and distribution of ssts were evaluated.

Anterior pituitary was positively stained for all 5 ssts. Pancreatic islets exhibited a positive staining for sst1–3 and sst5. Adrenal cortex expressed all 5 receptor subtypes, while the medulla was positive for sst3 and sst5 only. The thyroid expressed sst5 only, limited to single interfollicular cells. All 5 ssts were detected in the ovary, limited to luteinized granulosa cells of the corpus luteum. In the testis, sst2A was detected in the basal parts of the tubules, while sst5 was positively stained in the luminal parts. Sst1 was found in Leydig cells only. Stomach was positively stained for all 5 ssts. Investigation of the kidney revealed differential expression, with sst2A being found in the glomerules. The tubules expressed all 5 ssts. In the bone marrow cells of the granulocytopoiesis expressed sst2A only. The cerebellum expressed sst5 in a certain cell type, representing presumably Purkinje cells, while sst2A was stained in intercellular fibers.

The expression of somatostatin receptor subtypes in a variety of human normal tissues may indicate a physiological role in these organs. Somatostatin analogues may offer new diagnostic and therapeutic implications for tumours related to these tissues. However, treatment of defined tumours with somatostatin analogues may also alter other normal tissues.

Key words

sst1–5 - physiology - regulation - immunohistochemistry

Full Text

References

References
1 Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999; 20: 157-198
2 Bruns C, Raulf F, Hoyer D et al. Binding properties of somatostatin receptor subtypes. Metabolism 1996; 45: 17-20
3 Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab 2002; 87: 3013-3018
4 Oberg K, Kvols L, Caplin M et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 2004; 15: 966-973
5 Bruns C, Lewis I, Briner U et al. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 2002; 146: 707-716
6 Unger N, Serdiuk I, Sheu SY et al. Immunohistochemical localization of somatostatin receptor subtypes in benign and malignant adrenal tumours. Clin Endocrinol (Oxf) 2008; 68: 850-857
7 Schulz S, Handel M, Schreff M et al. Localization of five somatostatin receptors in the rat central nervous system using subtype-specific antibodies. J Physiol Paris 2000; 94: 259-264
8 Schulz S, Schulz S, Schmitt J et al. Immunocytochemical detection of somatostatin receptors sst1, sst2A, sst2B, and sst3 in paraffin-embedded breast cancer tissue using subtype-specific antibodies. Clin Cancer Res 1998; 4: 2047-2052
9 Schulz S, Pauli SU, Schulz S et al. Immunohistochemical determination of five somatostatin receptors in meningioma reveals frequent overexpression of somatostatin receptor subtype sst2A. Clin Cancer Res 2000; 6: 1865-1874
10 Kumar U, Sasi R, Suresh S et al. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes 1999; 48: 77-85
11 Le Romancer M, Cherifi Y, Levasseur S et al. Messenger RNA expression of somatostatin receptor subtypes in human and rat gastric mucosae. Life Sci 1996; 58: 1091-1098
12 Pfeiffer M, Koch T, Schroder H et al. Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J Biol Chem 2001; 276: 14027-14036
13 Pfeiffer M, Koch T, Schroder H et al. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem 2002; 277: 19762-19772
14 Schulz S, Schmidt H, Handel M et al. Differential distribution of alternatively spliced somatostatin receptor 2 isoforms (sst2A and sst2B) in rat spinal cord. Neurosci Lett 1998; 257: 37-40
15 Schulz S, Helmholz T, Schmitt J et al. True positive somatostatin receptor scintigraphy in primary breast cancer correlates with expression of sst2A and sst5. Breast Cancer Res Treat 2002; 72: 221-226
16 Schulz S, Schmitt J, Quednow C et al. Immunohistochemical detection of somatostatin receptors in human ovarian tumors. Gynecol Oncol 2002; 84: 235-240
17 Mundschenk J, Unger N, Schulz S et al. Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab 2003; 88: 5150-5157
18 Kulaksiz H, Eissele R, Rossler D et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut 2002; 50: 52-60
19 Lupp A, Hunder A, Petrich A et al. Reassessment of sst(5) Somatostatin Receptor Expression in Normal and Neoplastic Human Tissues Using the Novel Rabbit Monoclonal Antibody UMB-4. Neuroendocrinology 2011; 94: 255-264
20 Rohrer SP, Birzin ET, Mosley RT et al. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 1998; 282: 737-740
21 Rossowski WJ, Coy DH. Specific inhibition of rat pancreatic insulin or glucagon release by receptor-selective somatostatin analogs. Biochem Biophys Res Commun 1994; 205: 341-346
22 Mercado M, Borges F, Bouterfa H et al. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol (Oxf) 2007; 66: 859-868
23 Schopohl J, Strasburger CJ, Caird D et al. Efficacy and acceptability of lanreotide Autogel(R) 120 mg at different dose intervals in patients with acromegaly previously treated with octreotide LAR. Exp Clin Endocrinol Diabetes 2011; 119: 156-162
24 Kreienkamp HJ, Akgun E, Baumeister H et al. Somatostatin receptor subtype 1 modulates basal inhibition of growth hormone release in somatotrophs. FEBS Lett 1999; 462: 464-466
25 Petersenn S, Schopohl J, Barkan A et al. Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial. J Clin Endocrinol Metab 2010; 95: 2781-2789
26 Hofland LJ, van der Hoek J, Feelders R et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol 2005; 152: 645-654
27 Boscaro M, Ludlam WH, Atkinson B et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009; 94: 115-122
28 O’Carroll AM, Krempels K. Widespread distribution of somatostatin receptor messenger ribonucleic acids in rat pituitary. Endocrinology 1995; 136: 5224-5227
29 Park S, Kamegai J, Kineman RD. Role of glucocorticoids in the regulation of pituitary somatostatin receptor subtype (sst1-sst5) mRNA levels: evidence for direct and somatostatin-mediated effects. Neuroendocrinology 2003; 78: 163-175
30 Panetta R, Patel YC. Expression of mRNA for all five human somatostatin receptors (hSSTR1-5) in pituitary tumors. Life Sci 1995; 56: 333-342
31 Mato E, Matias-Guiu X, Chico A et al. Somatostatin and somatostatin receptor subtype gene expression in medullary thyroid carcinoma. J Clin Endocrinol Metab 1998; 83: 2417-2420
32 Ain KB, Taylor KD, Tofiq S et al. Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines. J Clin Endocrinol Metab 1997; 82: 1857-1862
33 Taniyama Y, Suzuki T, Mikami Y et al. Systemic distribution of somatostatin receptor subtypes in human: an immunohistochemical study. Endocr J 2005; 52: 605-611
34 Korner M, Eltschinger V, Waser B et al. Value of immunohistochemistry for somatostatin receptor subtype sst2A in cancer tissues: lessons from the comparison of anti-sst2A antibodies with somatostatin receptor autoradiography. Am J Surg Pathol 2005; 29: 1642-1651
35 Orlando C, Raggi CC, Bianchi S et al. Measurement of somatostatin receptor subtype 2 mRNA in breast cancer and corresponding normal tissue. Endocr Relat Cancer 2004; 11: 323-332
36 Kumar U, Grigorakis SI, Watt HL et al. Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1–5 and correlation with receptor protein expression and tumor pathology. Breast Cancer Res Treat 2005; 92: 175-186
37 Prevost G, Foehrle E, Thomas F et al. Growth of human breast cancer cell lines is inhibited by the somatostatin analog BIM23014. Endocrinology 1991; 129: 323-329
38 Weckbecker G, Liu R, Tolcsvai L et al. Antiproliferative effects of the somatostatin analogue octreotide (SMS 201-995) on ZR-75-1 human breast cancer cells in vivo and in vitro. Cancer Res 1992; 52: 4973-4978
39 Bajetta E, Procopio G, Ferrari L et al. A randomized, multicenter prospective trial assessing long-acting release octreotide pamoate plus tamoxifen as a first line therapy for advanced breast carcinoma. Cancer 2002; 94: 299-304
40 Ruan W, Fahlbusch F, Clemmons DR et al. SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?. Mol Endocrinol 2006; 20: 426-436
41 Goddard I, Bauer S, Gougeon A et al. Somatostatin inhibits stem cell factor messenger RNA expression by Sertoli cells and stem cell factor-induced DNA synthesis in isolated seminiferous tubules. Biol Reprod 2001; 65: 1732-1742
42 Fombonne J, Csaba Z, von Boxberg Y et al. Expression of somatostatin receptor type-2 (sst2A) in immature porcine Leydig cells and a possible role in the local control of testosterone secretion. Reprod Biol Endocrinol 2003; 1: 19
43 Baou N, Bouras M, Droz JP et al. Evidence for a selective loss of somatostatin receptor subtype expression in male germ cell tumors of seminoma type. Carcinogenesis 2000; 21: 805-810
44 Fischer T, Doll C, Jacobs S et al. Reassessment of sst2 Somatostatin Receptor Expression in Human Normal and Neoplastic Tissues Using the Novel Rabbit Monoclonal Antibody UMB-1. J Clin Endocrinol Metab 2008;
45 Reynaert H, Rombouts K, Vandermonde A et al. Expression of somatostatin receptors in normal and cirrhotic human liver and in hepatocellular carcinoma. Gut 2004; 53: 1180-1189
46 Yamada Y, Post SR, Wang K et al. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci USA 1992; 89: 251-255
47 Raderer M, Hejna MH, Muller C et al. Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. Int J Oncol 2000; 16: 1197-1201
48 Blaker M, Schmitz M, Gocht A et al. Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas. J Hepatol 2004; 41: 112-118
49 Verhoef C, van Dekken H, Hofland LJ et al. CH. Somatostatin receptor in human hepatocellular carcinomas: biological, patient and tumor characteristics. Dig Surg 2008; 25: 21-26
50 Balster DA, O’Dorisio MS, Summers MA et al. Segmental expression of somatostatin receptor subtypes sst(1) and sst(2) in tubules and glomeruli of human kidney. Am J Physiol Renal Physiol 2001; 280: F457-F465
51 Bhandari S, Watson N, Long E et al. Expression of somatostatin and somatostatin receptor subtypes 1-5 in human normal and diseased kidney. J Histochem Cytochem 2008; 56: 733-743
52 Reubi JC, Horisberger U, Studer UE et al. Human kidney as target for somatostatin: high affinity receptors in tubules and vasa recta. J Clin Endocrinol Metab 1993; 77: 1323-1328
53 Rolleman EJ, Kooij PP, de Herder WW et al. Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney. Eur J Nucl Med Mol Imaging 2007; 34: 1854-1860
54 Freudenberg LS, Gauler T, Gorges R et al. Somatostatin receptor scintigraphy in advanced renal cell carcinoma. Results of a phase II-trial of somatostatine analogue therapy in patients with advanced RCC. Nuklearmedizin 2008; 47: 127-131
55 Smith WH, Nair RU, Adamson D et al. Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts. J Endocrinol 2005; 187: 379-386
56 Colao A, Marzullo P, Ferone D et al. Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly. J Clin Endocrinol Metab 2000; 85: 3132-3140
57 Varecza Z, Elekes K, Laszlo T et al. Expression of the somatostatin receptor subtype 4 in intact and inflamed pulmonary tissues. J Histochem Cytochem 2009; 57: 1127-1137