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Horm Metab Res 2005; 37(12): 722-728
DOI: 10.1055/s-2005-921092
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Differential Expression of the Human Somatostatin Receptor Subtypes sst1 to sst5 in Various Adrenal Tumors and Normal Adrenal Gland

B.  Ueberberg1 , H.  Tourne1 , A.  Redman1 , M.  K.  Walz2 , K.  W.  Schmid3 , K.  Mann1 , S.  Petersenn1
  • 1Division of Endocrinology, Medical Center, University of Essen, Essen, Germany
  • 2Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany
  • 3Institute of Pathology, University of Essen, Essen, Germany
Further Information

Publication History

Received 7 March 2005

Accepted after revision 9 August 2005

Publication Date:
22 December 2005 (online)

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ErratumHorm Metab Res 2006; 38(09): 617-617
DOI: 10.1055/s-2006-956173

Abstract

Somatostatin (SRIF) is a widely distributed peptide with growth-inhibiting effects in various tumors. So far, five distinct human SRIF receptor subtypes (sst1 - sst5) have been identified. We investigated expression of the five ssts in various adrenal tumors and in normal adrenal gland. Tissue was obtained from ten pheochromocytomas (PHEOs), nine cortisol-secreting adenomas (CPAs), eleven aldosterone secreting adenomas (APAs) and eight non-functional adenomas (NFAs) after retroperitoneoscopic surgery, and used for RNA extraction. Adrenal tissue surrounding the tumor was available for analysis in twenty-seven cases. Receptor expression was studied by RT-PCR using sst-specific primers and subsequently confirmed by Southern blotting. Expression of all five receptor subtypes was observed in RNA obtained from normal adrenal gland. Furthermore, each receptor subtype was expressed in more than 50 % of all tumors analyzed. No sst5 expression was found in PHEOs, while sst1 was present in nearly all of these tumors. Only a few of the CPAs expressed subtypes sst1 and sst4. Expression of all five subtypes was distributed equally in APAs. No sst4 was found in any of the NFAs. Differential expression of ssts in various adrenal tumors may point to new aspects in the pathogenesis of these adenomas. Furthermore, the presence of specific ssts could expand the diagnostic and therapeutic strategies during management. New subtype specific analogues of SRIF may be used in the future depending on the type of adrenal tumor and receptor subtype expressed.

Key words

Somatostatin receptor - somatostatin analogues - adrenal gland - adrenal tumor - pheochromocytoma - aldosterone - cortisol - expression

References

  • 1 Reubi J C, Laissue J A. Multiple actions of somatostatin in neoplastic disease.  Trends Pharmacol Sci. 1995;  16 110-115
    CrossrefPubMedSearch in Google Scholar
  • 2 Meyerhof W. The elucidation of somatostatin receptor functions: a current view.  Rev Physiol Biochem Pharmacol. 1998;  133 55-108
    PubMedSearch in Google Scholar
  • 3 Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P, Petcher T J, Pless J. SMS 201 - 995: a very potent and selective octapeptide analogue of somatostatin with prolonged action.  Life Sci. 1982;  31 1133-1140
    CrossrefPubMedSearch in Google Scholar
  • 4 Heiman M L, Murphy W A, Coy D H. Differential binding of somatostatin agonists to somatostatin receptors in brain and adenohypophysis.  Neuroendocrinology. 1987;  45 429-436
    PubMedSearch in Google Scholar
  • 5 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. 2002;  146 707-716
    Search in Google Scholar
  • 6 Sharma K, Patel Y C, Srikant C B. Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3.  Mol Endocrinol. 1996;  10 1688-1696
    CrossrefPubMedSearch in Google Scholar
  • 7 Panetta R, Patel Y C. Expression of mRNA for all five human somatostatin receptors (hSSTR1-5) in pituitary tumors.  Life Sci. 1995;  56 333-342
    PubMedSearch in Google Scholar
  • 8 Kumar U, Sasi R, Suresh S, Patel A, Thangaraju M, Metrakos P, Patel S C, Patel Y C. 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
    CrossrefPubMedSearch in Google Scholar
  • 9 Balster D A, O'Dorisio M S, Summers M A, Turman M A. 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
    PubMedSearch in Google Scholar
  • 10 Epelbaum J, Bertherat J, Prevost G, Kordon C, Meyerhof W, Wulfsen I, Richter D, Plouin P F. Molecular and pharmacological characterization of somatostatin receptor subtypes in adrenal, extraadrenal, and malignant pheochromocytomas.  J Clin Endocrinol Metab. 1995;  80 1837-1844
    CrossrefPubMedSearch in Google Scholar
  • 11 Kimura N, Schindler M, Kasai N, Kimura I. Immunohistochemical localization of somatostatin receptor type 2A in rat and human tissues.  Endocr J. 2001;  48 95-102
    PubMedSearch in Google Scholar
  • 12 Sestini R, Orlando C, Peri A, Tricarico C, Pazzagli M, Serio M, Pagani A, Bussolati G, Granchi S, Maggi M. Quantitation of somatostatin receptor type 2 gene expression in neuroblastoma cell lines and primary tumors using competitive reverse transcription-polymerase chain reaction.  Clin Cancer Res. 1996;  2 1757-1765
    PubMedSearch in Google Scholar
  • 13 Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein S R. The clinically inapparent adrenal mass: update in diagnosis and management.  Endocr Rev. 2004;  25 309-340
    CrossrefPubMedSearch in Google Scholar
  • 14 Koch C A, Pacak K, Chrousos G P. The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors.  J Clin Endocrinol Metab. 2002;  87 5367-5384
    CrossrefPubMedSearch in Google Scholar
  • 15 Walz M K, Peitgen K, Walz M V, Hoermann R, Saller B, Giebler R M, Jockenhovel F, Philipp T, Broelsch C E, Eigler F W, Mann K. Posterior retroperitoneoscopic adrenalectomy: lessons learned within five years.  World J Surg. 2001;  25 728-734
    CrossrefPubMedSearch in Google Scholar
  • 16 O'Carroll A M. Localization of messenger ribonucleic acids for somatostatin receptor subtypes (sstr1 - 5) in the rat adrenal gland.  J Histochem Cytochem. 2003;  51 55-60
    PubMedSearch in Google Scholar
  • 17 Zatelli M C, Piccin D, Bondanelli M, Tagliati F, De Carlo E, Culler M D, Uberti E C. An in vivo OctreoScan-negative adrenal pheochromocytoma expresses somatostatin receptors and responds to somatostatin analogs treatment in vitro.  Horm Metab Res. 2003;  35 349-354
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Reubi J C, Waser B, Schaer J C, Laissue J A. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands.  Eur J Nucl Med. 2001;  28 836-846
    CrossrefPubMedSearch in Google Scholar
  • 19 Mundschenk J, Unger N, Schulz S, Hollt V, Steinke R, Lehnert H. Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy.  J Clin Endocrinol Metab. 2003;  88 5150-5157
    CrossrefPubMedSearch in Google Scholar
  • 20 Unger N, Serdiuk I, Sheu S Y, Walz M K, Schulz S, Schmid K W, Mann K, Petersenn S. Immunohistochemical determination of somatostatin receptor subtypes 1, 2A, 3, 4, and 5 in various adrenal tumors.  Endocr Res. 2004;  30 931-934
    CrossrefPubMedSearch in Google Scholar
  • 21 Maurea S, Lastoria S, Caraco C, Klain M, Varrella P, Acampa W, Muto P, Salvatore M. The role of radiolabeled somatostatin analogs in adrenal imaging.  Nucl Med Biol. 1996;  23 677-680
    PubMedSearch in Google Scholar
  • 22 van der Harst E, de Herder W W, Bruining H A, Bonjer H J, de Krijger R R, Lamberts S W, van de Meiracker A H, Boomsma F, Stijnen T, Krenning E P, Bosman F T, Kwekkeboom D J. [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas.  J Clin Endocrinol Metab. 2001;  86 685-693
    CrossrefPubMedSearch in Google Scholar
  • 23 Boksa P, St-Pierre S, Livett B G. Characterization of substance P and somatostatin receptors on adrenal chromaffin cells using structural analogues.  Brain Res. 1982;  245 275-283
    CrossrefPubMedSearch in Google Scholar
  • 24 Pisarek H, Pawlikowski M. Immunohistochemical localization of the somatostatin receptor subtype 2A in the rat adrenal gland.  Folia Histochem Cytobiol. 2002;  40 27-30
    PubMedSearch in Google Scholar
  • 25 Rebuffat P, Robba C, Mazzocchi G, Nussdorfer G G. Inhibitory effect of somatostatin on the growth and steroidogenic capacity of rat adrenal zona glomerulosa.  J Steroid Biochem. 1984;  21 387-390
    CrossrefPubMedSearch in Google Scholar
  • 26 Mazzocchi G, Robba C, Rebuffat P, Gottardo G, Nussdorfer G G. Effect of somatostatin on the zona glomerulosa of rats treated with angiotensin II or captopril: stereology and plasma hormone concentrations.  J Steroid Biochem. 1985;  23 353-356
    CrossrefPubMedSearch in Google Scholar
  • 27 Reubi J C, Maurer R, von Werder K, Torhorst J, Klijn J G, Lamberts S W. Somatostatin receptors in human endocrine tumors.  Cancer Res. 1987;  47 551-558
    PubMedSearch in Google Scholar
  • 28 Maurer R, Reubi J C. Somatostatin receptors in the adrenal.  Mol Cell Endocrinol. 1986;  45 81-90
    CrossrefPubMedSearch in Google Scholar
  • 29 Aguilera G, Harwood J P, Catt K J. Somatostatin modulates effects of angiotensin II in adrenal glomerulosa zone.  Nature. 1981;  292 262-263
    PubMedSearch in Google Scholar
  • 30 Boscaro M, Scaroni C, Edwards C R, Mantero F. Inhibitory effect of somatostatin on the aldosterone response to angiotensin II: in vitro studies.  J Endocrinol Invest. 1982;  5 173-177
    PubMedSearch in Google Scholar
  • 31 Jones C R, Millar J A, Lawrie C, Sumner D J, Reid J L. Specific inhibition of aldosterone responses to endogenous and exogenous angiotensin II by somatostatin.  Clin Endocrinol (Oxf). 1984;  21 279-284
    PubMedSearch in Google Scholar
  • 32 Rebuffat P, Mazzocchi G, Gottardo G, Nussdorfer G G. Further studies on the involvement of dopamine and somatostatin in the inhibitory control of the growth and steroidogenic capacity of rat adrenal zona glomerulosa.  Exp Clin Endocrinol. 1989;  93 73-81
    PubMedSearch in Google Scholar
  • 33 Kasprzak A, Rebuffat P, Andreis P G, Mazzocchi G, Nussdorfer G G. Effects of prolonged cysteamine administration on the rat adrenal cortex: evidence that endogenous somatostatin is involved in the control of the growth and steroidogenic capacity of zona glomerulosa.  J Steroid Biochem Mol Biol. 1991;  38 469-473
    CrossrefPubMedSearch in Google Scholar
  • 34 Mazzocchi G, Malendowicz L K, Meneghelli V, Nussdorfer G G. Evidence that endogenous somatostatin (SRIF) exerts a tonic inhibitory effect on the rat renin-angiotensin-aldosterone system.  In Vivo. 1992;  6 9-12
    PubMedSearch in Google Scholar
  • 35 Rebuffat P, Belloni A S, Musajo F G, Rocco S, Markowska A, Mazzocchi G, Nussdorfer G G. Evidence that endogenous somatostatin (SRIF) exerts an inhibitory control on the function and growth of rat adrenal zona glomerulosa. The possible involvement of zona medullaris as a source of endogenous SRIF.  J Steroid Biochem Mol Biol. 1994;  48 353-360
    CrossrefPubMedSearch in Google Scholar
  • 36 Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos G P, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis.  J Clin Endocrinol Metab. 1997;  82 3054-3058
    CrossrefPubMedSearch in Google Scholar
  • 37 Zwermann O, Beuschlein F, Klink A, Stahl M, Reincke M. The role of the ACTH receptor in adrenal tumors: identification of a novel microsatellite marker.  Horm Metab Res. 2004;  36 406-410
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Lin S R, Hsu C H, Tsai J H, Wang J Y, Hsieh T J, Wu C H. Decreased GTPase activity of K-ras mutants deriving from human functional adrenocortical tumours.  Br J Cancer. 2000;  82 1035-1040
    CrossrefPubMedSearch in Google Scholar
  • 39 Reincke M, Karl M, Travis W H, Mastorakos G, Allolio B, Linehan H M, Chrousos G P. p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies.  J Clin Endocrinol Metab. 1994;  78 790-794
    CrossrefPubMedSearch in Google Scholar
  • 40 Boulle N, Logie A, Gicquel C, Perin L, Le Bouc Y. Increased levels of insulin-like growth factor II (IGF-II) and IGF-binding protein-2 are associated with malignancy in sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 1998;  83 1713-1720
    CrossrefPubMedSearch in Google Scholar
  • 41 Fottner C, Hoeflich A, Wolf E, Weber M M. Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis.  Horm Metab Res. 2004;  36 397-405
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Kamio T, Shigematsu K, Sou H, Kawai K, Tsuchiyama H. Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma.  Hum Pathol. 1990;  21 277-282
    CrossrefPubMedSearch in Google Scholar
  • 43 Peri A, Luciani P, Conforti B, Baglioni-Peri S, Cioppi F, Crescioli C, Ferruzzi P, Gelmini S, Arnaldi G, Nesi G, Serio M, Mantero F, Mannelli M. Variable expression of the transcription factors cAMP response element-binding protein and inducible cAMP early repressor in the normal adrenal cortex and in adrenocortical adenomas and carcinomas.  J Clin Endocrinol Metab. 2001;  86 5443-5449
    CrossrefPubMedSearch in Google Scholar

PD Dr. med. Stephan Petersenn

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