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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 775-780
Copyright © 1999 by The Endocrine Society

Original Studies

Immunohistochemical Detection of Somatostatin Receptor Subtypes sst1 and sst2A in Human Somatostatin Receptor Positive Tumors

L.J. Hofland, Q. Liu, P.M. van Koetsveld, J. Zuijderwijk, F. van der Ham, R.R. de Krijger, A. Schonbrunn and S.W.J. Lamberts

Department of Internal Medicine III (L.J.H., P.M.K., J.Z., S.W.J.L.) and Pathology (F.H., R.R.K.), Erasmus University Rotterdam, Rotterdam 3015 GD, The Netherlands, and Department of Integrative Biology and Pharmacology (A.S., Q.L.), University of Texas, Houston, Texas 77225

Address all correspondence and requests for reprints to: L.J. Hofland, Ph.D., Department of Internal Medicine III, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: hofland{at}inw3.azr.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although in situ hybridization has been used to examine the distribution of messenger RNA for somatostatin receptor subtypes (sst) in human tumors, the cellular localization of sst1 and sst2A receptors has not been reported. In this study, we describe the cellular localization of human sst1 and sst2A receptor proteins in both cryostat- and paraffin-embedded sections of 25 human tumor tissues using two recently developed polyclonal antibodies. Six somatostatin (SS) receptor (SSR) positive tumors (two gastrinomas, three carcinoids, one pheochromocytoma) and one SSR negative tumor (renal cell carcinoma), selected by positive and negative SSR autoradiography, respectively, were studied by both immunohistochemistry and Western blot analysis. The six SSR positive tumors expressed sst2A, while 4 of 5 expressed sst1 as well. The SSR negative tumor did not express either sst1 or sst2A. Western blot analysis of wheat germ agglutinin purified membrane proteins confirmed the presence of the sst1 and sst2A glycosylated receptors. The paraffin-embedded sections gave best information with respect to the subcellular localization. Sst1 immunoreactivity was observed both on the membrane and in the cytoplasm, while sst2A showed predominantly membrane-associated immunoreactivity. This subcellular distribution of sst1 or sst2A receptors was confirmed in paraffin-embedded sections of 8 additional intestinal carcinoids, 5 gastrinomas and 5 pheochromocytomas. Sst1 receptors were detected in 7 out of 8 carcinoids, in all gastrinomas, and in 4 out of 5 pheochromocytomas, while 6 out of 8 carcinoids, all gastrinomas, and 3 out of 5 pheochromocytomas expressed sst2A receptors. In conclusion, sst1 and sst2A receptors show a differential subcellular localization in human SSR positive tumors. The use of SSR subtype selective antibodies to detect the subcellular distribution of SSR subtypes in individual tumor cells is an important step forward to understand more about the pathophysiological role of the different SSR subtypes in human tumors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A large number of human neuroendocrine tumors express somatostatin (SS) receptors (SSR) (1). Five SSR subtype genes, named sst1–5 have been identified and characterized (2). Two isoforms of sst2 (sst2A and sst2B) are generated by alternative splicing. Until now, the detection of SSR in human tumors has been performed either by ligand binding to membrane homogenates or tissue slices to detect combined SSR binding activity, or by messenger RNA (mRNA) analysis using either in situ hybridization (ISH), RNAse protection, or reverse transcriptase polymerase chain reaction (RT-PCR) to detect mRNA for each receptor subtype. While the use of in vitro SSR autoradiography and ISH has provided significant information regarding the heterogeneity of SSR expressed in tumors (1, 3), the precise cellular localization of SSR’s has been difficult to establish. Recently, two SSR subtype specific polyclonal antibodies have been developed (4, 5). The sst1 antibody (code-named R1–201) was raised against a 15-amino acid peptide corresponding to a unique sequence in the carboxyl terminus and characterized by immunoprecipitation of photoaffinity-labeled sst1 receptor (4). The sst2A antibody (code-named R2–88) was raised against a 22-amino acid peptide located in the C-terminal region of the rat sst2A receptor and characterized by immunopreciptation of photoaffinity labeled sst2A receptor as well as by immunoblot and immunohistochemistry (IHC) on cells transfected with complementary DNA encoding sst2A (5, 6). The peptide sequences used to raise both antibodies are conserved in the rat, mouse, and human forms (4, 5). The sst2A antibody has recently been used to detect sst2A in rat brain, pancreas, and pituitary sections (6, 7, 8). In this study we have used both antibodies to characterize the subcellular localization of sst1 and sst2A in human neuroendocrine tumors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tumor samples

Tumor tissue was obtained immediately after surgical removal and either frozen in liquid nitrogen through isopentane or fixed in 4% paraformaldehyde (PF) overnight. Diagnosis was made on the basis of clinical and biochemical characteristics of the patients, in combination with IHC of the tumor samples. All patients gave their informed consent for the use of tumor material for research purposes.

Immunohistochemistry

Frozen material. Five-micrometer cryostat sections were air-dried, fixed for 10 min with 10% PF, washed once with tap water, once with phosphate buffered saline (PBS), and incubated for 15 min in normal goat serum (1:10 dilution in PBS + 5% BSA). Thereafter, the sections were incubated overnight at 4 C with the sst1 (R1–201) and sst2A (R2–88) antibodies in a dilution of 1:1000. Finally, a standard streptavidin-biotinylated-peroxidase complex (ABC) kit (Biogenix, San Ramon, CA) was used according to the manufacturers instructions to visualize the bound antibodies.

Paraffin-embedded material. Five-micrometer sections were deparafinized, dehydrated, exposed to microwave heating (in citric acid buffer, 10 min at 100 C), rinsed in tap water (1x) and PBS (1x), and processed further as described above for the cryostat sections (sst1 and 2A antibody dilutions: 1:500). Negative controls for IHC included omission of the primary antibody and preabsorbtion of the antibodies with the respective immunizing receptor peptides (at a concentration of 0.3 µg/mL = 100 nM).

Western blot analyis

Membranes were prepared from human tumors or cell lines transfected to overexpress either the rat sst2A receptor (GH-R2) or the rat sst1 receptor (GH-R1) (4, 5, 6). Glycosylated proteins were purified by wheat germ agglutining (WGA) affinity chromatography as previously decribed (8). Either unpurified or WGA-purified membrane proteins were subjected to electrophoresis on 12% SDS polyacrylamide gels and then transferred to polyvinylidene difluoride (PVDF) membranes electrophoretically (4, 5, 6). After blocking, blots were incubated overnight at 4 C with 1:10,000 dilution of the appropiate antibody. Immunoblots were blocked, washed, and developed as described previously (5, 6, 7, 8).

SSR autoradiography

SSR autoradiography was carried out as described previously (9). Ten-micrometer sections were mounted onto precleaned gelatin coated microscope slides and stored at -80 C. To wash out endogenous somatostatin, the sections were preincubated at room temperature for 10 min in 170 mM Tris-HCl pH 7.4. Thereafter, the sections were incubated for 60 min at room temperature in 170 mM Tris-HCl pH 7.4, 5 mM MgCl2, 1% BSA, 40 µg/mL bacitracin in the presence of [125I-Tyr3]-octreotide (about 80–160 pmol/L) or [125I-Tyr0]SS28 (final concentration 80–160 pmol/L; ANAWA Laboratories, Wangen, Switzerland). Nonspecific binding was determined in a sequential section in the presence of excess unlabeled Tyr3-octreotide (1 µM) or SS-28 (1 µM). The incubated sections were washed twice for 5 min in incubation buffer containing 0.25% BSA and once in incubation buffer without BSA. After a short wash with distilled water to remove salt, the sections were air dried and exposed to Kodak X-OMAT AR or HyperfilmTM-3H (Amersham, Buckinghamshire, United Kingdom) for 3–7 days in x-ray cassettes. Histology was performed on hematoxylin-azophloxine stained sequential cryosections.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Seven human neuroendocrine tumors of different origin were selected on the basis of positive and negative SSR autoradiography (Table 1Go). Figure 1Go shows the localization of sst1 (Fig 1Go, A, B, E) and sst2A receptors (Fig. 1Go, C, D, F) in a human gastrinoma. For sst1 receptors immunohistochemical staining was observed both in the cytoplasm and at the cell membrane. This was seen most clearly in the paraffin-embedded sections (1B). Sst2A receptors were preferentially localized at the cell membrane (1D). Both intestinal carcinoids examined by IHC-expressed sst1 and all three carcinoids tested expressed sst2A (Table 1Go). The other gastrinoma expressed sst2A as well. The localization of sst1 receptors in the sst1-positive carcinoid was primarily cytoplasmic as well (1G). In addition, mainly membrane-localized sst2A receptors were found in the pheochromocytoma (1H). The pheochromocytoma was slightly sst1 positive as well. Neither sst1 nor sst2A immunostaining was observed in the stromal compartment of any of the tumors, although the endothelial cells of some tumoral vessels were sst2A positive (not shown). The renal cell carcinoma, which was selected on the basis of negative SSR autoradiography using [125I-Tyr0]somatostatin-28 and [125I-Tyr3]octreotide showed no positive staining by either the sst1 and sst2A antibody (Table 1Go).


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  		Table 1. SSR subtype sst1 and sst2A expression in human tumors as determined by SSR autoradiography, immunohistochemistry (IHC), and Western blotting

 


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  		Figure 1. Localization of sst1 and sst2A subtypes in a human SSR positive tumors. Immunohistochemical detection of sst1 (R1–201 antibody) and sst2A (R2–88 antibody) using two recently developed polyclonal antibodies (4 5 6 7 8 ) in human neuroendocrine tumors. A-D, gastrinoma, paraffin-embedded sections; E-F, gastrinoma, cryostat sections (A, B, E: sst1, C, D, F: sst2A). G; sst1 immunoreactivity in paraffin-embedded section of a human carcinoid; H, sst2A immunoreactivity in paraffin-embedded section of a human pheochromocytoma. Note the primarily cytoplasmic immunohistochemical localization of sst1 and the preferentially membrane-associated sst2A immunoreactivity.

 
To enrich the tumor extracts for the glycosylated receptor proteins, solubilized membrane proteins were partially purified by WGA-affinity chromatography before immunoblotting. Figure 2Go compares the results of the sst1 and sst2A analysis in a gastrinoma and an intestinal carcinoid to the staining observed in an SSR negative pituitary cell line (GH12C1) transfected to express either sst1 and sst2A. In each case, the most darkly stained band shows the broad migration pattern and size range characteristic of sst receptors. Immunostaining of this band was completely inhibited by 0.5–1 µM antigen peptide (Fig. 2Go). Data from all tumors examined are summarized in Table 1Go. The apparent molecular weight (Mw) for each receptor subtype varied between tumors: the observed Mw for sst1 ranged from 45 to 80 kDa, whereas that for sst2A varied from 60 to 85 kDa. This variability is consistent with differential glycosylation occuring in individual tumors and resembles what was previously observed in tumor cell lines (4, 5) and rat tissues (6, 7, 8).



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  		Figure 2. Immunoblot analysis of sst1 and sst2A in human tumors. Either unpurified membrane protein (GH-R2 cells, 5 µg) or WGA-purified membrane proteins (GH-R1 cells, gastrinoma, or carcinoid, purified from 35 µg, 300 µg, and 100 µg of membrane protein, respectively) were separated on a 12% SDS polyacrylamide gel. After transfer to polyvinylidene difluoride (PVDF) membrane, the proteins were immunoblotted with 1:10,000 dilution of sst1- (R1–201) or sst2A (R2–88) antibody in the absence (-) or presence (+) of either 1 µM sst1 peptide or 0.5 µM sst2A peptide antigen. Mw markers (in kDa) are shown on the left.

 
To further confirm the differential subcellular localization of sst1 and sst2A receptors in the tumor cells, we performed immunohistochemical analysis of both receptor subtypes in paraffin-embedded sections of eight additional intestinal carcinoids, five gastrinomas, and five pheochromocytomas. Sst1 receptors were detected in seven out of eight carcinoids, in all gastrinomas (n = 5), and in four out of five pheochromocytomas. Positive immunostaining for sst2A receptors was found in 6 out of 8 carcinoids, in all gastrinomas (n = 5), and in three out of five pheochromocytomas. This is shown in Table 2Go. In all tumors specificity of the staining with the sst1-specific antibody (R1–201) and with the sst2A-specific antibody (R2–88) was confirmed by the abolishment of immunostaining when the antibodies were pre-absorbed with 100 nM of the respective immunizing peptides. Figure 3Go shows examples of the neutralization of the predominant cytoplasmic staining for sst1-receptors in an intestinal carcinoid (Fig. 3Go, A, B) and in a gastrinoma (Fig. 3Go, C, D), as well as for the predominant membrane-associated staining of sst2A-receptors in a gastrinoma (Fig. 3Go, E, F) and a pheochromocytoma (Fig. 3Go, G, H). In the tumors studied, irrespective of the tumor type, we confirmed the primarily cytoplasmic localization of sst1 receptors and the preferential localization of sst2A receptors at the cell membrane.


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  		Table 2. Immunohistochemical detection of SSR subtypes sst1 and sst2A in paraffin embedded sections of human neuroendocrine tumors

 


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  		Figure 3. Displacement of immunohistochemical staining of sst1 (R1–201 antibody) and sst2A (R2–88 antibody) subtypes in human SSR positive tumors by preabsorbtion of the antibodies with 100 nM of the respective immunizing peptides. A and B, intestinal carcinoid (sst1); C and D, gastrinoma (sst1); E and F, gastrinoma (sst2A); G and H, pheochromocytoma (sst2A).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Along with the widespread actions of SS, many SS-target tissues as well as many neuroendocrine tumors often originating in these target tissues, have been shown to express SSR’s (1, 10). Until now SSR detection has been performed using ligand binding studies on membrane preparations or on frozen sections. In addition, the recent cloning and characterization of the genes of five SSR subtypes (2) has provided molecular biological tools, i.e. RT-PCR and ISH techniques, to study SSR subtype expression in normal and tumoral tissues (3). Moreover, the development of SSR subtype specific antibodies (4, 5, 6, 7, 8) now allows a detailed study of the cell types and cellular localization of SSR subtype proteins. In the present study we describe the cellular localization of sst1 and sst2A receptors in human neuroendocrine tumors of different origin. Specificity of the sst1 and sst2A antibodies was confirmed by immunohistochemical identification of approximately 60 and 85 kDa receptor proteins, respectively, in tumors by Western blotting experiments. The high frequency of expression of sst1 and sst2A receptor proteins in gastrinomas and carcinoids is in agreement with a predominant expression of sst1 and sst2A mRNAs in these tumor types (11).

The presence and possible functional significance of SSR’s and SSR subtypes expressed in normal and tumoral neuroendocrine tissues has been reviewed (2, 10, 12). While sst2A and sst5 are involved in the inhibition of hormone secretion, the functional role of the other SSR subtypes is less clear. In cells transfected with SSR subtype genes, agonist activation of sst1, sst2A, and sst5 seems involved in the antiproliferative action of SS(-analogs) via distinct as well as overlapping mechanisms (2). Whether such mechanisms also occur in human tumor cells expressing these particular subtypes remains to be established.

In the present study we found immunoreactive sst1 primarily in the cytoplasm, whereas sst2A was predominantly expressed at the cell membrane, irrespective of the tumor type. The membrane-localization of sst2 is in agreement with a recent study by Janson et al. (13) in human carcinoid tumors. The precise functional significance of our observations is unclear. The cytoplasmic sst1 may represent either neosynthesized or internalized receptors, as suggested previously to explain the cytoplasmic localization of sst2A in specific rat brain neurons in regions with high somatostatin expression (14). However, previous studies with COS or CHO cells transfected with individual SSR subtypes have shown that sst1 is internalized more poorly than sst2A after hormone binding (15, 16). If endogenous receptors in tumors behaved similarly, one would predict that more of the sst2A than the sst1 receptor would be internalized in tumors expressing both receptor subtypes. Instead we found the inverse distribution. Moreover, agonist exposure upregulates sst1 expression in CHO-K1 cells expressing this SSR subtype (16), while chronic SS exposure of GH4C1 pituitary cells increases SSR numbers (17). This increase in SSR number in GH4C1 cells was independent of new protein synthesis, and a potential mechanism could be changes in the intracellular distribution of SSRs (17). In this respect our observation of a predominant cytoplasmic localization of sst1 receptors in human tumor cells may also reflect a capacity of the tumor cells expressing this SSR subtype to increase SSR numbers after agonist exposure. This suggests that treatment of sst1 receptor-expressing cells with sst1-selective agonists may not result in a desensitization to treatment as has been observed in the majority of patients with islet-cell tumors and carcinoids treated with sst2-selective octapeptide SS-analogs (18). Clearly additional studies will be needed to establish whether this differential localization of sst1 and sst2A is a general phenomenon and to determine the biochemical mechanisms responsible.

In summary, the use of SSR subtype specific antibodies now allows a detailed examination of the subcellular localization of SSR subtypes in individual cells. This is an important step toward understanding more about the functional role of the individual SSR subtypes in human SSR positive tumors.

Received May 12, 1998.

Revised September 3, 1998.

Accepted November 11, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Reubi JC, Laissue J, Krenning E, Lamberts SWJ. 1992 Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications. J Steroid Biochem Mol Biol. 43:27–35.[CrossRef][Medline]
  2. Reisine T, Bell GI. 1995 Molecular biology of somatostatin receptors. Endocr Rev. 16:427–442.[CrossRef][Medline]
  3. Reubi JC, Schaer JC, Waser B, Mengod G. 1994 Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res. 54:3455–3459.[Abstract/Free Full Text]
  4. Gu Y-Z, Brown PJ, Loose-Mitchell DS, Stork PJS, Schonbrunn A. 1995 Development and use of a receptor antibody to characterize the interaction between somatostatin receptor subtype 1 and G proteins. Mol Pharmacol. 48:1004–1014.[Abstract]
  5. Gu Y-Z, Schonbrunn A. 1997 Coupling specificity between somatostatin receptor sst2A and G proteins: isolation of the receptor-G protein complex with a receptor antibody. Mol Endocrinol. 11:527–537.[Abstract/Free Full Text]
  6. Dournaud P, Gu YZ, Schonbrunn A, Mazella J, Tannenbaum GS, Beaudet A. 1996 Localization of the somatostatin receptor sst2A in rat brain using a specific anti-peptide antibody. J Neurosci. 16:4468–4478.[Abstract/Free Full Text]
  7. Mezey E, Hunyady B, Mitra S, et al. 1998 Cell specific expression of the sst2A and sst5 somatostatin receptors in the rat anterior pituitary. Endocrinology. 139:414–419.[Abstract/Free Full Text]
  8. Hunyady B, Hipkin RW, Schonbrunn A, Mezey E. 1997 Immunohistochemical localization of somatostatin receptor sst2A in the rat pancreas. Endocrinology. 138:2632–2635.[Abstract/Free Full Text]
  9. Hofland LJ, de Herder, WW, Visser-Wisselaar HA, et al. 1997 Dissociation between the effects of somatostatin (SS) and octapeptide SS-analogs on hormone release in a small subgroup of pituitary and islet cell tumors. J Clin Endocrinol Metab. 82:3011–3018.[Abstract/Free Full Text]
  10. Lamberts SWJ, Krenning EP, Reubi JC. 1991 The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev. 12:450–482.[CrossRef][Medline]
  11. Schaer J-C, Waser B, Mengod G, Reubi JC. 1997 Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography. Int J Cancer. 70:530–537.[CrossRef][Medline]
  12. Hofland LJ, Visser-Wisselaar HA, Lamberts SWJ. 1995 Somatostatin analogs: clinical application in relation to human human somatostatin receptor subtypes. Biochem Pharmacol. 50:287–297.[CrossRef][Medline]
  13. Janson ET, Stridsberg M, Gobl A, Westlin J-E, Oberg K. 1998 Determination of somatostatin receptor subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies. Cancer Res. 58:2375–2378.[Abstract/Free Full Text]
  14. Dournaud P, Boudin H, Schonbrunn A, Tannenbaum GS, Beaudet A. 1998 Interrelationships between somatostatin sst2A receptors and somatostatin containing axons in rat brain: evidence for regulation of cell surface receptors by endogenous somatostatin. J Neurosci. 18:1056–1071.[Abstract/Free Full Text]
  15. Nouel D, Gaudriault G, Houle M, et al. 1997 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. 138:296–306.[Abstract/Free Full Text]
  16. Hucovic N, Panetta R, Kumar U, Patel YC. 1996 Agonist-dependent regulation of cloned human somatostatin receptor types 1–5 (hSSTR1–5): subtype selective internalization or upregulation. Endocrinology. 137:4046–4049.[Abstract]
  17. Presky DH, Schonbrunn A. 1988 Somatostatin pretreatment increases the number of somatostatin receptors in GH4C1 pituitary cells and does not reduce cellular responsiveness to somatostatin. J Biol Chem. 263:714–721.[Abstract/Free Full Text]
  18. Lamberts SWJ, van der Lely AJ, de Herder WW, Hofland LJ. 1996 Octreotide. N Engl J Med. 334:246–254.[Free Full Text]



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