Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies

Abstract

Background and aims: Recently, novel somatostatin receptor (sstr) subtype specific ligand analogues have been developed for medical treatment of neuroendocrine tumours expressing different sstrs (sstr1-5). At present, individual expression patterns of sstr subtypes are based on methods such as in situ hybridisation and polymerase chain reaction at the transcriptional level. Therefore, we generated subtype specific antibodies against sstr1, 2A, 3, and 5 and analysed their presence, cellular localisation, distribution, and expression pattern in 33 gastrinomas, 36 insulinomas, and 35 tumours associated with a carcinoid syndrome by immunohistochemistry at the translational level. Methods: Western blotting experiments were performed in the normal human pancreas used as a reference organ and in tumour tissues; at the cellular level, sstrs were localised by immunohistochemistry in tissue paraffin sections. Results: In western blot analyses, the antibodies identified the respective receptors in their correct molecular range in extracts of the pancreas and neuroendocrine tumours. Using immunohistochemistry and immunofluorescence, the antibodies specifically detected the receptors in islet cells of the normal pancreas. Immunohistochemistry in the tumours revealed that all investigated sstr subtypes were highly expressed in the different tumour types. The frequency and expression pattern of the individual sstr subtypes varied considerably not only between the different tumour types but also in each patient. Conclusions: We conclude that immunohistochemistry with subtype specific antibodies can be used in clinical routine work to analyse sstr expression patterns for each patient before treatment and to facilitate well directed individual medical therapy by administering subtype specific somatostatin analogues.

Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy

“…23 Among alternative methods, immunohistochemistry seems to be a reliable tool to detect the somatostatin receptor profile in neuroendocrine tumors, due to the following advantages: detection of the receptor protein (instead of RNA, for example in PCR-based methods), possibility of detecting the cellular type expressing the receptor (neoplastic cells vs blood vessels or reactive lymphocytes, etc), availability of subtype specific antibodies, applicability in archival material, low cost/benefit ratio which renders this method applicable in most laboratories. 13,[15][16][17]19,21 On the contrary, major disadvantages are related to the lack of standardization of the method (from both technical and interpretation viewpoints) which is a great limitation in diagnostic applications, the failure of demonstrating 'functional' receptors (as opposed to autoradiography), and undetermined sensitivity of the technique, since limited evidence has been reported on the correlation between immunohistochemistry and other in vivo techniques. In a recent paper, Korner et al 15 tested different somatostatin receptor type 2A antibodies in different human tumors, and correlated the immunohistochemical pattern with previous autoradiographic data on 37 cases, demonstrating a good correlation between the two methods applying the same antibody selected in our study.…”

“…In a recent paper, Korner et al 15 tested different somatostatin receptor type 2A antibodies in different human tumors, and correlated the immunohistochemical pattern with previous autoradiographic data on 37 cases, demonstrating a good correlation between the two methods applying the same antibody selected in our study. Previous reports testing somatostatin receptor immunohistochemistry in lung 18 and gastrointestinal 16 neuroendocrine tumors and in pheochromocytomas 17 in correlation to somatostatin receptor scintigraphy are limited by the relative low number of cases compared and by a general lack of standardization of the immunohistochemical interpretation (ie membranous vs cytoplasmic pattern). Therefore, we designed the present study on a large multicentric series of neuroendocrine tumors to validate the reproducibility of the immunohistochemical method and to compare the results with somatostatin receptor scintigraphy imaging.…”

“…Several studies have documented that generally these methods correlate each other in somatostatin receptors positive cases, with only minor discrepancies. [13][14][15][16][17][18][19][20][21][22] The currently available somatostatin analogues bind preferentially somatostatin receptors type 2 (which is the most widely expressed subtype in neuroendocrine tumors) and to a lower extent types 3 and 5, and somatostatin receptors profiling in individual patients may be of relevance to better tailor the somatostatin analogue-based treatment. This would hopefully allow to increase the response rate of each patient and reduce costs of biotherapy, which are generally high.…”

Metastatic Carcinoid Tumors: A Clinical Review

“…Octreotide analogues have a high affinity for the SSR-2 and SSR-5 receptor subtypes and a much lower binding to the SSR-1, SSR-3, and SSR-4 subtypes [40]. 111 In-pentetreotide (a radioactive-labeled octreotide analogue) shares the receptor-binding profile of octreotide, which makes it a good radiopharmaceutical for the imaging of carcinoid tumors.…”

Differential β-Arrestin Trafficking and Endosomal Sorting of Somatostatin Receptor Subtypes

“…Five genes encoding six different somatostatin receptor subtypes (sst 1 , sst 2A , sst 2B , sst 3 , sst 4 , sst 5 ) have been cloned. These receptors are widely expressed in the central nervous system and periphery, and multiple somatostatin receptor subtypes often coexist in the same cell (1,2).…”