Abstract
Somatostatin receptors subtype 2 (SSTR2) expression in somatotropinomas is recognized as a predictor of response to the currently available somatostatin analogs and may be analyzed, mainly, by quantitative RT-PCR or immunohistochemistry (IHC). The former has the advantages of a higher sensitivity and of being quantitative, while the latter, although semi-quantitative, evaluates protein expression and is routinely used in the evaluation of pituitary adenomas. We aimed to evaluate the SSTR2A protein expression in somatotropinomas and to compare it to our previous data regarding mRNA expression, assessed by quantitative real time RT-PCR. Thirteen somatotropinomas were analyzed by IHC and the tumors were scored according to percent of immunostained cells: 0 (<25%), 1 (25–50%) and 2 (>50%). SSTR2A immunostaining was present in all but one somatotropinoma, 4 (31 %) tumors were classified as score 0, 4 (31%) as score 1, and 5 (38%) as score 2. Median SSTR2 mRNA content was significantly different among the three IHC scores (p=0.036) and was lower in the score 0 than in the score 2 (p=0.016). The finding that there is a positive correlation between RT-PCR and IHC indicates that IHC can be applied in order to assess the SSTR2A content in somatotropinomas.
Similar content being viewed by others
References
Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999, 20: 157–98.
Reisine T, Bell GI. Molecular properties of somatostatin receptors. Neuroscience 1995, 67: 777–90.
Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W. Regulation and function of somatostatin receptors. J Neurochem 2004, 89: 1057–91.
Duran-Prado M, Saveanu A, Luque RM, et al. A potential inhibitory role for the new truncated variant of somatostatin receptor 5, sst5TMD4, in pituitary adenomas poorly responsive to somatostatin analogs. J Clin Endocrinol Metab 2010, 95: 2497–502.
Neto LV, Machado Ede O, Luque RM, et al. Expression analysis of dopamine receptor subtypes in normal human pituitaries, nonfunctioning pituitary adenomas and somatotropinomas, and the association between dopamine and somatostatin receptors with clinical response to octreotide-LAR in acromegaly. J Clin Endocrinol Metab 2009, 94: 1931–7.
de Bruin C, Pereira AM, Feelders RA, et al. Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab 2009, 94: 1118–24.
Taboada GF, Luque RM, Bastos W, et al. Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol 2007, 156: 65–74.
Taboada GF, Luque RM, Neto LV, et al. Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol 2008, 158: 295–303.
Jaquet P, Saveanu A, Gunz G, et al. Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab 2000, 85: 781–92.
Vieira Neto L, Taboada GF and Gadelha MR. Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR responsiveness in acromegaly. Arq Bras Endocrinol Metabol 2008, 52: 1288–95.
Ferone D, de Herder WW, Pivonello R, et al. Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J Clin Endocrinol Metab 2008, 93: 1412–7.
Takei M, Suzuki M, Kajiya H, et al. Immunohistochemical detection of somatostatin receptor (SSTR) subtypes 2A and 5 in pituitary adenoma from acromegalic patients: good correlation with preoperative response to octreotide. Endocr Pathol 2007, 18: 208–16.
Resmini E, Dadati P, Ravetti JL, et al. Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient. J Clin Endocrinol Metab 2007, 92: 1592–9.
Greenman Y, Melmed S. Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 1994, 79: 724–9.
Greenman Y, Melmed S. Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 1994, 78: 398–403.
Corbetta S, Ballare E, Mantovani G, et al. Somatostatin receptor subtype 2 and 5 in human GH-secreting pituitary adenomas: analysis of gene sequence and mRNA expression. Eur J Clin Invest 2001, 31: 208–14.
Miller GM, Alexander JM, Bikkal HA, Katznelson L, Zervas NT, Klibanski A. Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab 1995, 80: 1386–92.
Park C, Yang I, Woo J, et al. Somatostatin (SRIF) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide. Endocr J 2004, 51: 227–36.
Casarini AP, Jallad RS, Pinto EM, et al. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 2009, 12: 297–303.
Thodou E, Kontogeorgos G, Theodossiou D, Pateraki M. Mapping of somatostatin receptor types in GH or/and PRL producing pituitary adenomas. J Clin Pathol 2006, 59: 274–9.
Pisarek H, Stepien T, Kubiak R, Borkowska E, Pawlikowski M. Expression of somatostatin receptor subtypes in human thyroid tumors: the immunohistochemical and molecular biology (RT-PCR) investigation. Thyroid Res 2009, 2: 1.
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: 175–86.
Papotti M, Bongiovanni M, Volante M, 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 Arch 2002, 440: 461–75.
Papotti M, Croce S, Macri L, et al. Correlative immunohistochemical and reverse transcriptase polymerase chain reaction analysis of somatostatin receptor type 2 in neuroendocrine tumors of the lung. Diagn Mol Pathol 2000, 9: 47–57.
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 1994, 54: 3455–9.
Korner M, Eltschinger V, Waser B, Schonbrunn A, Reubi JC. 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: 1642–51.
Barlier A, Pellegrini-Bouiller I, Gunz G, Zamora AJ, Jaquet P, Enjalbert A. Impact of gsp oncogene on the expression of genes coding for Gsalpha, Pit-1, Gi2alpha, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity. J Clin Endocrinol Metab 1999, 84: 2759–65.
Reubi JC, Waser B, Cescato R, Gloor B, Stettler C, Christ E. Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients. J Clin Endocrinol Metab 2010, 95: 2343–50.
Hukovic N, Panetta R, Kumar U and Patel YC. Agonist-dependent regulation of cloned human somatostatin receptor types 1–5 (hSSTR1-5): subtype selective internalization or upregulation. Endocrinology 1996, 137: 4046–9.
Nouel D, Gaudriault G, Houle M, et al. Differential internalization of somatostatin in COS-7 cells transfected with SST1 and SST2 receptor subtypes: a confocal microscopic study using novel fluorescent somatostatin derivatives. Endocrinology 1997, 138: 296–306.
Nagel F, Doll C, Pöll F, Kliewer A, Schröder H, Schulz S. Structural determinants of agonist-selective signaling at the sst(2A) somatostatin receptor. Mol Endocrinol 2011, 25: 859–66.
Waser B, Tamma ML, Cescato R, Maecke HR, Reubi JC. Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. J Nucl Med 2009, 50: 936–41.
Liu Q, Cescato R, Dewi DA, Rivier J, Reubi JC, Schonbrunn A. Receptor signaling and endocytosis are differentially regulated by somatostatin analogs. Mol Pharmacol 2005, 68: 90–101.
Author information
Authors and Affiliations
Corresponding author
Additional information
L.E.A.W. and L.V.N. have contributed equally to the manuscript.
Rights and permissions
About this article
Cite this article
Wildemberg, L.E.A., Neto, L.V., Costa, D.F. et al. Validation of immunohistochemistry for somatostatin receptor subtype 2A in human somatotropinomas: Comparison between quantitative real time RT-PCR and immunohistochemistry. J Endocrinol Invest 35, 580–584 (2012). https://doi.org/10.3275/7906
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.3275/7906