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Monoclonal antibodies against the human somatostatin receptor subtypes 1–5: Development and immunohistochemical application in neuroendocrine tumors

Schmid, Herbert and Lambertini, Chiara and Van Vugt, Harmke and Barzaghi-Rinaudo, Patrizia and Schaefer, Judith and Stumm, Michael and Sailer, Andreas and Kaufmann, Martina and Nuciforo, Paolo (2011) Monoclonal antibodies against the human somatostatin receptor subtypes 1–5: Development and immunohistochemical application in neuroendocrine tumors. Neuroendocrinology. ISSN 0028-3835

Abstract

Activation of somatostatin receptors (sstr1–5) by somatostatin and its analogues exerts an inhibitory effect on hormone secretion and provides the basis for the treatment of a range of endocrine diseases, such as acromegaly, Cushing’s disease and neuroendocrine tumors (NET). The lack of well characterized commercially available sstr subtype-specific antibodies, however, has prevented a routine expression profile of sstrs in patients.
To address this need, we generated and characterized new mouse monoclonal antibodies (mAbs) targeting the five human sstr subtypes. All mAbs were tested intensively by ELISA and immunohistochemistry for specificity and were found to selectively recognize their cognate receptor subtype with no cross-reactivity. The suitability of the mAbs to investigate sstrs expression in formalin-fixed and paraffin-embedded (FFPE) human tissues was then demonstrated by staining archival samples of normal pancreatic tissue and NET. The expression profile of sstr1–5 using these mAbs was analyzed using tissue microarray technology in a series of gastrointestinal neuroendocrine tumors (NET) (n=67) and correlated with clinicopathologic data. With the exception of sstr3, all receptor subtypes were expressed in NET (54%, 83%, 0%, 54% and 63% of tumors were positive for sstr1, sstr2a, sstr3, sstr4 and sstr5, respectively), with sstr1, sstr2a and sstr5 being present both at the plasma membrane and in the cytoplasm of tumor cells. Protein levels of sstr1, sstr2a and sstr4 tended to decrease as tumor aggressiveness increased, while sstr5 showed an opposite pattern, with higher expression in well differentiated carcinomas compared with well differentiated tumors. Similarly, a correlation between sstr5 expression and the presence of metastases and angioinvasion was demonstrated, suggesting the possible involvement of this specific receptor subtype in more aggressive behavior in NET. Further data are required to confirm this hypothesis.
We conclude that determination of the sstr1–5 expression profile by immunohistochemistry using subtype-specific mAbs is feasible in FFPE tissue. This finding suggests new opportunities to explore the significance of sstr expression in the development and progression of NET providing a tool for routine clinical practice.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author or institutional server; Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4048

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