Skip to main content

Advertisement

Log in

Validation of immunohistochemistry for somatostatin receptor subtype 2A in human somatotropinomas: Comparison between quantitative real time RT-PCR and immunohistochemistry

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999, 20: 157–98.

    Article  PubMed  Google Scholar 

  2. Reisine T, Bell GI. Molecular properties of somatostatin receptors. Neuroscience 1995, 67: 777–90.

    Article  PubMed  Google Scholar 

  3. Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W. Regulation and function of somatostatin receptors. J Neurochem 2004, 89: 1057–91.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. 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.

    PubMed  Google Scholar 

  10. 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.

    Article  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. 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.

    PubMed  Google Scholar 

  15. Greenman Y, Melmed S. Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 1994, 78: 398–403.

    PubMed  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. 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.

    PubMed  Google Scholar 

  18. 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.

    Article  PubMed  Google Scholar 

  19. 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.

    Article  PubMed  Google Scholar 

  20. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  21. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  Google Scholar 

  25. 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.

    PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. 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.

    PubMed  Google Scholar 

  28. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  29. 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.

    PubMed  Google Scholar 

  30. 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.

    PubMed  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. 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.

    Article  PubMed  Google Scholar 

  33. 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.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. R. Gadelha MD, PhD.

Additional information

L.E.A.W. and L.V.N. have contributed equally to the manuscript.

Rights and permissions

Reprints 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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3275/7906

Key-words

Navigation