This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kimura, N. Articles by Schindler, M. Search for Related Content PubMed PubMed Citation Articles by Kimura, N. Articles by Schindler, M.

Immunohistochemical Expression of Somatostatin Type 2A Receptor in Neuroendocrine Tumors

Department of Pathology, Tohoku University School of Medicine, and Tohoku Rosai Hospital, Sendai 981-8563 [N. K., M. P., F. D.]; Department of Neurology, National Yamagata Hospital, Yamagata 990-0876, Japan [I. K.]; and Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge CB2 10J, United Kingdom [M. S.]

	ABSTRACT

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Somatostatin (SS) and SS analogues inhibit the growth of various kinds of endocrine and exocrine cells via the SS receptor (SSTR). Carcinoid tumor is representative of the tumors treatable by SS analogues. We examined the expression of SSTR2A by immunohistochemical and in situ hybridization methods with a specific antibody against a synthesized 20-amino acid peptide of the COOH terminus of human SSTR2A and oligonucleotide probes in 62 endocrine tumors of various kinds: pancreatic endocrine tumor; carcinoid; neuroendocrine carcinoma; medullary thyroid carcinoma; pheochromocytoma; and small cell carcinoma of the lung, neuroblastoma, and ganglioneuroma. SSTR2A was expressed in 87% of these tumors and at both primary and metastatic sites. The immunohistochemical reactivity of SSTR2A was strong on the cell membrane and less intense in the cytoplasm of the tumor cells. SSTR2A mRNA was also detected in the tumor cells. The results indicate the usefulness of SSTR2A analogues for the treatment of neuroendocrine tumors, even metastatic ones: metastatic carcinoids, metastatic pheochromocytomas, tumors that adhered to large vessels, and neuroendocrine carcinomas.

	INTRODUCTION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The biological behavior of neuroendocrine tumors, such as carcinoid tumors and pancreatic endocrine tumors, and pheochromocytomas has generally resulted in a good prognosis. The surgical removal of neuroendocrine tumors is often curative when the tumor is detected at an early stage. However, if such tumors have distant metastases in the liver, lung, or bone, neither anticancer chemotherapy or irradiation therapy has much of an effect. An analysis of 5-year survival rates in patients with malignant neuroendocrine tumors revealed that the survival rates are <20% when liver metastases are present (1) . Neuroendocrine carcinoma, which is composed of small poorly differentiated neuroendocrine cells, is also a highly aggressive tumor with a poor prognosis (2) . Capella et al. (3) proposed a new classification of the neuroendocrine tumors or the lung, pancreas, and gut. They classified neuroendocrine tumors of the pancreas, colon, and rectum as benign, benign or low-grade malignant, low-grade malignant, and high-grade malignant. High-grade malignant tumors are compatible with neuroendocrine carcinoma. Regarding metastatic pheochromocytomas, there are two types of tumors; one is a slowly progressive tumor, even with bone or lung metastases, and the other is an extremely aggressive tumor with a poor prognosis (4) . There is as yet no effective treatment for either type of metastatic pheochromocytoma.

SS² has a broad spectrum of biological actions, exerts suppressive effects on multiple organs including the brain, pituitary, gut, exocrine and endocrine pancreas, adrenals, thyroid, and kidneys, and appears to be an endogenous growth inhibitor (5) . SS exerts its biological effects by binding to specific high-affinity receptors, which appear in many cases to be coupled to GTP-binding proteins. SS and SS analogues effectively inhibit the proliferation of various types of cancer cells (5) . All of these effects are mediated by specific high-affinity SSTRs on the target tissue (6) .

Molecular cloning has revealed the presence of at least five different types of SSTRs in the rat, all of which belong to the seven-transmembrane domain receptor superfamily and are expressed in the central nervous system. They have been named SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 (7 , 8) . Sequence comparisons of the SSTR subtypes have revealed two subgroups of receptors in the SSTR gene family. SSTR1 and SSTR4 share common characteristics that differ from those of the subgroup containing the subtypes SSTR2, SSTR3, and SSTR5. Short peptide analogues such as octreotide demonstrate specific binding only for the subgroup consisting of SSTR2, SSTR3, and SSTR5 (6) . SSTR2 is shown to be directly involved in the transduction of the antiproliferative effects (9) . Although there have been investigations of the localization of SSTR by autoradiography, PCR, and in situ hybridization (10, 11, 12) , few studies have been done on the cellular localization of the receptor subtype proteins in neuroendocrine tumors, especially in metastatic or highly malignant neuroendocrine tumors (13 , 14) . In the present study, using an anti-peptide polyclonal antibody specific for SSTR2A, we investigated the distribution of this receptor protein in various types of neuroendocrine tumors by immunohistochemistry. The presence of SSTR2 mRNA was also investigated in representative cases of neuroendocrine tumors by an in situ hybridization method. The data obtained could contribute to the assessment of the utility of SS analogues for highly malignant neuroendocrine tumors.

	MATERIALS AND METHODS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The majority of the specimens investigated were surgically obtained; some of the highly malignant tumors were obtained by autopsy. Autopsies were carried out within 3 h after death. Those specimens were from the files of the Department of Pathology, Tohoku University. The 62 neuroendocrine tumors examined included 16 pancreatic endocrine tumors, of which 3 had metastases (an ACTH-producing tumor with Cushing’s syndrome metastasizing to the liver and lymph nodes, a gastrin-producing tumor metastasizing to the liver, and an insulin-producing tumor with lymph node metastases); 20 carcinoid tumors, 11 from the rectum (2 had liver metastases), 2 thymus (with multiple metastases), 2 small intestine, 3 ovary, and 2 testis; 3 neuroendocrine carcinomas (primary sites were the stomach, gall bladder, and unknown origin); 2 medullary thyroid carcinomas; 2 small cell carcinomas of the lung, which were positive for chromogranin A; 15 pheochromocytomas (3 had metastases to the bone, lung, and liver); 2 neuroblastomas of undifferentiated type; and 2 ganglioneuromas. For the positive control specimens for SSTR2A, normal pancreas tissues obtained by autopsy, fixed by 10% buffered formalin, and embedded in paraffin were used.

Immunohistochemistry.
The formalin-fixed, paraffin-embedded tissues were dewaxed and rehydrated. The antigen retrieval of the sections was accomplished by incubation in 0.01 M citric acid buffer (pH 6.0) and autoclaving for 5 min at 120°C, before the immunohistochemical procedures. The immunohistochemical staining for SSTR2A was carried out by the streptavidin-biotin-complex method as reported previously (15) . The sheep polyclonal antibody against SSTR2A was raised against a synthetic peptide corresponding to the predicted amino acids 347–366 of the COOH terminus of rat SSTR2A (16) . This peptide sequence is identical in the rat, human, and mouse SSTR2A. The working dilution of SSTR2A was 1:200. A rabbit antisheep IgG-biotinylated antibody (1:100; Vector Laboratories, Burlingame, CA) was used as the second antibody. Nuclei were slightly counterstained with hematoxylin. The specificity of the affinity-purified SSTR2A antibody has been demonstrated by Western blotting and adsorption testing using 100 µM SSTR2A peptide to block the antibody (at a dilution of 1:300) for 18h at 4°C (16) . Additional controls included the omission of the primary antibody. To reveal the colocalization of immunoreactive SSTR2A and pancreatic peptide hormones, serial sections were cut, and pairs of adjacent sections were examined for SSTR2A and peptide hormones insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, and ACTH. The sources and working dilutions of these peptide hormones were as follows: insulin (1:3000; DAKO, Glostrup, Denmark), glucagon (1:3000; DAKO), somatostatin (1:3000; DAKO), pancreatic polypeptide (1:4000; DAKO), gastrin (1:3000; DAKO), and ACTH (1:4000; Incstar, Stillwater, MN).

The immunoreactive intensity of each tumor of the pancreas was compared with that of normal pancreatic islets of tissue adjacent to the tumor and evaluated as "+++" if the intensity was more than that of the islets, "++" if the same as that of the islets, "+" if less than that of the islets. "-" indicated the absence of immunoreactivity. The immunoreactivity of the tumors of other sites was compared with that of the pancreatic endocrine tumors.

In Situ Hybridization Method.
On the basis of the human SSTR2 mRNA sequence cloned by Yamada et al. (17) , we used four synthesized oligonucleotide probes: 48-base long oligonucleotides complementary to the bases coding for amino acids 31–46 and 237–252 (18) ; 359–364 (compatible with the COOH-terminus of our antibody); and 1220–1224 (untranslated region) of the human SSTR2 mRNA sequence. Those oligonucleotides were labeled with DIG with the use of a DIG oligonucleotide tailing kit (Boehringer Mannheim, Mannheim, Germany) as recommended by the manufacturer and used as a mixture. The sense probe for SSTR2 (1220–1244) was used as a negative control.

In situ hybridization was carried out for some representative tumors (5 pancreatic endocrine tumors, 5 carcinoid tumors, and 5 pheochromocytomas). The procedure was described previously (15) . Briefly, deparaffinized sections were treated with 0.2 M HCl for 20 min at 37°C and then digested with proteinase K. After acetylation with 0.1 M triethanol amine solution with 0.25% acetic anhydride, the sections were prehybridized at 37°C for 1 h. Hybridization was performed for 18 h at 37°C, using DIG-labeled oligonucleotide probes at a concentration of 100 ng/ml, in a hybridization solution. The sense probe labeled with DIG was used as the control probe. After washing, the sections were processed for immunological detection. Briefly, the sections were incubated with a blocking solution and then incubated with alkaline phosphatase-labeled anti-DIG sheep IgG (Fab fragment). The visualization of the immune complex was performed using a biotin-streptavidin signal amplification system (Nichirei, Tsukiji, Tokyo) and alkaline phosphatase color reaction. Nuclei were slightly counterstained with hematoxylin.

	RESULTS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the normal pancreatic islets of the positive controls, the majority of islet cells showed strong immunoreactivity for SSTR2A in whole islets without immunohistochemical heterogeneity. Strong immunoreactivity was clearly detected on the cell membrane, whereas less intense staining was found in the cytoplasm (Fig. 1) . The immunohistochemistry results of SSTR2A in the pancreatic endocrine tumors and the other endocrine tumors are summarized in Tables 1 and 2 , respectively. Of the 16 pancreatic endocrine tumors, 15 showed SSTR2A immunoreactivity. Only one insulin-producing tumor was negative for SSTR2A. There was no distinct correlation between the expression of SSTR2A and peptide hormones produced by the tumors (Table 1) . All metastatic tumors including an ACTH-producing tumor, a gastrin-producing tumor, and an insulin-producing tumor showed strong immunoreactivity for SSTR2A not only in the primary tumors but also at the metastatic sites 2(Fig. 2) . Among the 20 carcinoid tumors (including 4 autopsy cases with distant metastases: 2 rectal and 2 thymic carcinoid tumors), all except the 2 autopsy cases (one rectal and one thymic carcinoid) showed moderate to strong immunoreactivity. All 3 neuroendocrine carcinomas of the stomach, gallbladder, or unknown origin obtained by autopsy with multiple metastases were positive for SSTR2A. One of two medullary thyroid carcinomas showed SSTR2A. One of two small cell carcinomas of the lung, which were composed of cells positive for chromogranin A, showed immunoreactivity for SSTR2A. Although there was immunoreactive heterogeneity, all pheochromocytomas showed immunoreactivity (Fig. 3) . Interestingly, a highly malignant pheochromocytoma obtained by autopsy showed strong immunoreactivity for SSTR2 not only in the primary tumor but also in the metastatic tumors in the liver and lung (Fig. 4) . This tumor was composed of small cells with an extremely high nuclear cytoplasmic ratio, diffusely positive for chromogranin A and sporadically positive for tyrosine hydroxylase, and metastasized to multiple organs. The patient with this tumor died of multiple tumor metastases 4 months after diagnosis. The other metastatic pheochromocytoma also showed strong immunoreactivity, even at metastatic sites of the lung. The neuroblastomas of undifferentiated type without ganglionic cell differentiation had no SSTR2A immunoreactivity. In contrast, the ganglionic cells of the ganglioneuroma showed strong immunoreactivity on the cell membrane (Fig. 5) . Of the 62 neuroendocrine tumors, 55 (88%) showed immunoreactivity for SSTR2 (Table 2) .

View larger version (116K): [in this window] [in a new window]   Fig. 1. SSTR2A immunoreactivity is observed in normal pancreas. The majority of islet cells and some ductal cells are strongly positive. Immunoreactive intensity is strong on the cell membrane and less in the cytoplasm (x100, slightly counterstained with hematoxylin).

View larger version (157K): [in this window] [in a new window]   Fig. 2. The majority of tumor cells of ACTH-producing pancreatic endocrine tumor show diffuse immunoreactivity for SSTR2A. The cell membrane is strongly stained and cytoplasm less intensely stained (x200, slightly counterstained with hematoxylin).

View larger version (148K): [in this window] [in a new window]   Fig. 3. The majority of tumor cells of pheochromocytoma demonstrate strong immunoreactivity for SSTR2A on the cell membrane (x200, slightly counterstained with hematoxylin).

View larger version (152K): [in this window] [in a new window]   Fig. 4. The metastatic tumor cells in the liver from a patient with a highly malignant pheochromocytoma demonstrate strong immunoreactivity for SSTR2A as well as the primary tumor in the adrenal gland (x400, slightly counterstained with hematoxylin).

View larger version (148K): [in this window] [in a new window]   Fig. 5. Well-differentiated ganglionic cells of ganglioneuroma show obvious staining of SSTR2A on their cell membrane (x200, slightly counterstained with hematoxylin).

View larger version (153K): [in this window] [in a new window]   Fig. 6. SSTR2A mRNA is presented in the majority of tumor cells of ACTH-producing pancreatic endocrine tumor as related by ISH (the same case as Fig. 2 , x100).

	DISCUSSION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The immunohistochemical localization of SSTR has been investigated in normal rat brain and spinal cord (16) , neurons of the myenteric and submucosal plexuses, interstitial cells of Cajal of the intestine, and enterochromaffin-like cells of the rat stomach (19) and the rat pancreas (20) . However, to our knowledge, there have been few immunohistochemical studies of SSTR2A in normal human tissues or neuroendocrine tumors. Hunyady et al. (20) reported SSTR2A in the rat pancreas, and that all acinar cells and glucagon (A)- and pancreatic polypeptide (PP)-immunoreactive cells were intensely labeled for SSTR2A, whereas no signal was detected in SS-producing cells. A very few insulin immunoreactive cells were also labeled for SSTR2A, but the signal in these cells was weaker than that in the exocrine, A, or PP cells. Our present findings revealed that the human pancreas is quite different from the rat pancreas regarding SSTR2A expression, and all islet cells in the human pancreas express SSTR2A. We also found that all but one of the pancreatic endocrine tumors expressed SSTR2A. In the other types of neuroendocrine tumors, the immunohistochemical expression of SSTR2A was also extremely high, and the expression is coincident with that of mRNA in these tumors as determined by us and also by Reubi et al. (18) .

A number of somatostatin analogues have been used for the treatment of acromegaly and endocrine tumors of the gastroenteropancreatic system (such as carcinoid tumors, insulinomas, glucagonomas, and VIPomas; Refs. 5 , 21 , and 22 ). Most of these tumors and cell lines express SSTR2 (18 , 23 , 24) , and mRNA for SSTR5 is also present in gastroenteropancreatic tumors (25) . The activation of a tyrosine phosphatase and the inhibition of calcium mobilization mediated by SSTR2 and SSTR5, respectively, could be important steps in the negative mitogenic signal induced by a somatostatin analogue (25) . Janson et al. (12) compared the efficacy of the expression of SSTR2 mRNA and the response to SS analogue treatment in patients with carcinoid tumors. They concluded that there was complete agreement between the presence of mRNA for SSTR2 detected by ISH and a positive therapeutic outcome. Recently, they further conducted a immunohistochemical study of SSTR2 in the above tumors and obtained the same results, concluding that the immunohistochemical method is applicable in clinical practice (14) .

Although there were no cases treated with somatostatin analogues in the present study, we would like to refer to the possible utility of somatostatin analogues not only for carcinoid tumors but also for malignant neuroendocrine tumors including metastatic pheochromocytoma, neuroendocrine carcinoma, and infiltrating ganglioneuroma, for which there are no effective treatments at present. Further practical investigations of somatostatin analogues for patients with such tumors should be conducted. The presence of the other types of SSTR should also be clarified in SSTR2A-negative tumors.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Department of Pathology, Tohoku Rosai Hospital, 21-3-4 Dainohara Aoba-Ku Sendai, 981-8563, Japan. Fax: 81-22-279-4991; E-mail: nkimura{at}patholo2.med.tohoku.ac.jp

² The abbreviations used are: SS, somatostatin; SSTR, SS receptor; ACTH, adrenocorticotrophic hormone; DIG, digoxigenin; ISH, in situ hybridization.

Received 5/27/99; accepted 8/24/99.

	REFERENCES

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Oberg K., Eriksson B., Janson E. T. The clinical use of interferons in the management of neuroendocrine gastroenteropancreatic tumors. Ann. NY Acad. Sci., 733: 471-478, 1994.[Medline]
2. Gould V. E., Jao W., Chejfec G., Banner B. F., Bonomi P. Neuroendocrine carcinoma of the gastrointestinal tract. Semin. Diag. Pathol., 1: 13-18, 1984.
3. Capella C., Heitz P. U., Hofler H., Solcia E., Kloppel G. Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Virchows Archiv., 425: 547-560, 1995.[Medline]
4. Kimura N., Miura W., Noshiro T., Miura Y., Ookuma T., Nagura H. Ki67 is an indicator of progression of neuroendocrine tumors. Endocr. Pathol., 5: 223-228, 1994.
5. Schally A. V. Oncological applications of somatostatin analogues. Cancer Res., 48: 6977-6985, 1988.
6. Bruns C., Weckbecker G., Raulf F., Kaupmann K., Schoeffter P., Hoyer D., Lubbert H. Molecular pharmacology of somatostatin-receptor subtypes. Ann. NY Acad. Sci., 733: 138-146, 1994.[Medline]
7. Hoyer D., Bell G. I., Berelowitz M., Epelbaum J., Feniuk W., Humphrey P. P. A., O’Carroll A. M., Patel Y., Schonbrunn A., Taylor J. E., Reisene T. Classification and nomenclature of somatostatin receptors. Trends Pharmacol. Sci., 16: 86-88, 1995.[Medline]
8. Reisine T., Bell G. Molecular biology of somatostatin receptors. Endocr. Rev., 16: 427-442, 1995.[Medline]
9. Buscail L., Saint-Laurent N., Chastre E., Vaillant J. C., Gespach C., Capella G., Kalthoff H., Lluis F., Vaysse N., Susini C. Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer. Cancer Res., 56: 1823-1827, 1996.[Abstract/Free Full Text]
10. Reubi J. C., Waser B., Lamberts S. W. J., Mengod G. Somatostatin (SRIH) messenger ribonucleic acid expression in human neuroendocrine and brain tumor using in situ hybridization histochemistry: comparison with SRIH receptor content. J. Clin. Endocrinol. Metab., 76: 642-647, 1993.[Abstract]
11. Reubi J. C. Relevance of somatostatin receptors and other peptide receptors in pathology. Endocr. Pathol., 8: 11-20, 1997.[Medline]
12. Janson E. T., Gobl A., Kalkner K. M., Oberg K. A comparison between the efficacy of somatostatin receptor scintigraphy and that of in situ hybridization for somatostatin receptor subtype 2 messenger RNA to predict therapeutic outcome in carcinoid patients. Cancer Res., 576: 2561-2565, 1996.
13. Reubi J. C., Kappeler A., Waser B., Laissue J., Hipkin R. W., Schonbrunn A. Immunohistochemical localization of somatostatin receptors sst2A in human tumors. Am. J. Pathol., 153: 233-245, 1998.[Abstract/Free Full Text]
14. Janson E. T., Stridsberg M., Gobl A., Westlin J. E., Oberg K. Determination of somatostatin receptor subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies. Cancer Res., 58: 2375-2378, 1998.[Abstract/Free Full Text]
15. Kimura N., Togo A., Sugimoto T., Nata K., Okamoto H., Nagatsu I., Nagura H. Deficiency of phenylethanolamine N-methyltransferase in norepinephrine-producing pheochromocytoma. Endocr. Pathol., 7: 131-136, 1996.[Medline]
16. Schindler M., Sellers L. A., Humphery P. A., Emson P. C. Immunohistochemical localization of the somatostatin SST_2(A) receptor in the rat brain and spinal cord. Neuroscience, 76: 225-240, 1997.[Medline]
17. Yamada Y., Post S. R., Wang K., Tager H. S., Bell G., Seino S. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc. Natl. Acad. Sci. USA, 89: 251-255, 1992.[Abstract/Free Full Text]
18. Reubi J. C., Schaer J. C., 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., 54: 3455-3459, 1994.[Abstract/Free Full Text]
19. Sternini C., Wong H., Wu S. V., de Giorgio R., Yang M., Reeve J., Jr., Brecha N. C., Walsh J. H. Somatostatin 2A receptor is expressed by enteric neurons, and by interstitial cells of Cajal and enterochromaffin-like cells of the gastrointestinal tract. J. Comp. Neurol., 386: 396-408, 1997.[Medline]
20. Hunyady B., Hipkin R. W., Schonbrunn A., Mezey E. Immunohistochemical localization of somatostatin receptor SST2A in the rat pancreas. Endocrinology, 138: 2632-2635, 1997.[Abstract/Free Full Text]
21. Yang I. M., Woo J. T., Kim S. W., Kim J. W., Kim Y. S., Choi Y. K. Characteristics of acromegalic patients with a good response to octreotide, a somatostatin analogue. Clin. Endocrinol., 42: 295-301, 1995.[Medline]
22. Nilsson O., Kolby L., Wangberg B., Wigander A., Billig H., William-Olsson L., Fjallng M., Forssell-Aronsson E., Ahlman H. Comparative studies on the expression of somatostatin receptor subtypes, outcome of octreotide scintigraphy and response to octreotide treatment in patients with carcinoid tumours. Br. J. Cancer, 77: 632-637, 1998.[Medline]
23. Eden P. A., Taylor J. E. Somatostatin receptor subtype gene expression in human and rodent tumors. Life Sci., 53: 85-90, 1993.[Medline]
24. Buscail L., Delesque N., Esteve J. P., Saint-Laurent N., Prats H., Clerc P., Robberecht P., Bell G. I., Liebow C., Schally A. V., Vaysse N., Susini C. . Proc. Natl. Acad. Sci. USA, 91: 2315-2319, 1994.[Abstract/Free Full Text]
25. Buscall L., Esteve J-P., Saint-Laurent N., Bertrand V., Reisine T., O’Carroll A. M., Bell G. I., Schally A. V., Vaysse N., Susine C. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc. Natl. Acad. Sci. USA, 92: 1580-1584, 1995.[Abstract/Free Full Text]

This article has been cited by other articles:

				E Thodou, G Kontogeorgos, D Theodossiou, and M Pateraki Mapping of somatostatin receptor types in GH or/and PRL producing pituitary adenomas. J. Clin. Pathol., March 1, 2006; 59(3): 274 - 279. [Abstract] [Full Text] [PDF]

				J. Mundschenk, N. Unger, S. Schulz, V. Hollt, S. Schulz, R. Steinke, and H. Lehnert Somatostatin Receptor Subtypes in Human Pheochromocytoma: Subcellular Expression Pattern and Functional Relevance for Octreotide Scintigraphy J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5150 - 5157. [Abstract] [Full Text] [PDF]

				J. C. Reubi Peptide Receptors as Molecular Targets for Cancer Diagnosis and Therapy Endocr. Rev., August 1, 2003; 24(4): 389 - 427. [Abstract] [Full Text] [PDF]

				L. J. Hofland and S. W. J. Lamberts The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance Endocr. Rev., February 1, 2003; 24(1): 28 - 47. [Abstract] [Full Text] [PDF]

				H Kulaksiz, R Eissele, D Rossler, S Schulz, V Hollt, Y Cetin, and R Arnold Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies Gut, January 1, 2002; 50(1): 52 - 60. [Abstract] [Full Text] [PDF]

				J. C. Reubi, B. Waser, Q. Liu, J. A. Laissue, and A. Schonbrunn Subcellular Distribution of Somatostatin sst2A Receptors in Human Tumors of the Nervous and Neuroendocrine Systems: Membranous Versus Intracellular Location J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3882 - 3891. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kimura, N. Articles by Schindler, M. Search for Related Content PubMed PubMed Citation Articles by Kimura, N. Articles by Schindler, M.