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      Growing vascular endothelial cells express somatostatin subtype 2 receptors

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          Abstract

          We hypothesized that non-proliferating (quiescent) human vascular endothelial cells would not express somatostatin receptor subtype 2 (sst 2) and that this receptor would be expressed when the endothelial cells begin to grow. To test this hypothesis, placental veins were harvested from 6 human placentas and 2 mm vein disks were cultured in 0.3% fibrin gels. Morphometric analysis confirmed that 50–75% of cultured vein disks developed radial capillary growth within 15 days. Sst 2 gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) analysis of the RNA from veins before culture and from tissue-matched vein disks that exhibited an angiogenic response. The sst 2 gene was expressed in the proliferating angiogenic sprouts of human vascular endothelium. The presence of sst 2 receptors on proliferating angiogenic vessels was confirmed by immunohistochemical staining and in vivo scintigraphy. These results suggest that sst 2 may be a unique target for antiangiogenic therapy with sst 2 preferring somatostatin analogues conjugated to radioisotopes or cytotoxic agents. © 2001 Cancer Research Campaign http://www.bjcancer.com

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          Somatostatin receptor gene expression in neuroblastoma.

          Anne R. Albers, M.Sue O’Dorisio, Douglas A. Balster … (2000)
          Somatostatin receptor expression is a favorable prognostic factor in human neuroblastoma. Somatostatin receptors have been demonstrated in vitro by pharmacologic analysis of tumor tissue and in vivo by diagnostic radioreceptor scintigraphy. However, which receptor subtypes (sst(1), sst(2), sst(3), sst(4), and sst(5)) are expressed in these tumors has not yet been delineated. We used RT-PCR to analyze expression of the five somatostatin receptor genes in 32 neuroblastoma tumor specimens. All 32 tumor specimens expressed mRNA for c-abl and sst(1); sst(2) mRNA was detected in 27/32 samples and somatostatin mRNA was detected in 30/32 tumor specimens. The remaining receptor subtypes, sst(3), sst(4), and sst(5) were variably expressed. Receptor protein for sst(1) and sst(2) was visualized in tumor neuroblasts as well as in endothelial cells of tumor vessels using immunostaining with specific anti-receptor antibodies. The effect of high expression of somatostatin receptors on cell proliferation was examined in SKNSH neuroblastoma cells transfected with sst(1) and sst(2). SS(14) binding to wild-type SKNSH cells was undetectable; but the native peptide bound with high affinity to the SKNSH/sst(1) and SKNSH/sst(2) neuroblastoma cell lines. Pharmacologic analysis of binding with two long-acting analogues, CH275 and octreotide, confirmed selective expression of sst(1) and sst(2) in stably transfected SKNSH cells. Formation of neuroblastoma xenograft tumors in nude mice was significantly delayed for both SKNSH/sst(1) (P<0.001) and SKNSH/sst(2) (P<0.05) cells compared to wild-type SKNSH. We conclude that: (1) Somatostatin receptors, sst(1) and sst(2), are expressed in the majority of neuroblastomas at diagnosis; and (2) upregulation of functional sst(1) or sst(2) in neuroblastoma cell lines suppresses tumorigenicity in a xenograft model. These observations suggest that somatostatin receptors may be a useful therapeutic target in neuroblastoma.
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            Somatostatin receptors and their subtypes in human tumors and in peritumoral vessels.

            B. Waser, J Reubi, Dominik J. Schaer … (1996)
            Somatostatin receptors are expressed by a large variety of human tumors. In vitro receptor autoradiographic studies have shown that these tumors can express more than one somatostatin receptor subtype. Whereas the majority of tumors bind octreotide with high affinity, some, i.e., prostate tumors, bind octreotide with low affinity only. The discovery of five somatostatin receptor subtypes, sst1-5, by gene cloning has increased our understanding of somatostatin receptor structure and function. Using in situ hybridization techniques, we found that various human tumors, identified as somatostatin receptor-positive in binding studies, expressed sst2 mRNA in the majority of cases, whereas sst1 and sst3 were less frequent. Often, all three sst were expressed simultaneously. In another recent in situ hybridization study, primary prostate cancers were shown to preferentially express sst1, rather than sst2 or sst3. Moreover, a high incidence of sst5 was found in growth hormone (GH)-producing pituitary adenomas and, to a lesser extent, in active pituitary adenomas; gastroenteropancreatic (GEP) tumors showed all possible combinations, but with a predominance of sst2. Overall, the presence of sst2 mRNA and/or sst5 generally correlated with the presence of octreotide-binding sites, but with exceptions. These results indicate the highly variable abundance of sst mRNAs in individual somatostatin receptor-containing tumors. Somatostatin receptors were not only found in tumoural tissue, but also in the peritumoral vascular system. This was particularly well studied in colorectal carcinomas, where the peritumoral veins were shown to express in all cases a high density of somatostatin receptors, probably of the sst2 type, binding octreotide with high affinity. Therefore, the host peritumoral vascular system may be a possible target of somatostatin action in tumor development. Somatostatin may act locally on tumor growth through two different mechanisms dependent on local somatostatin receptor expression: through direct action on tumor cells or through action on peritumoral vessels, which may alter the hemodynamics of the tumoral blood circulation.
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              Expression of somatostatin receptors in peritumoral veins of human tumors.

              J Reubi, B Denzler (1999)
              The vascular system of the tumor bed plays an important function in tumor growth regulation. Recent studies have suggested that the vasoactive peptides somatostatin and substance P may have a potential role in the tumor bed of selected tumors. In the current study, somatostatin receptors were evaluated with in vitro receptor autoradiography using 125I-[Tyr3]-octreotide in the peritumoral vessels of a large group of 215 primary human tumors and 25 metastases of various tumor origin, with particular emphasis on receptor incidence, distribution, homogeneity, and density. High affinity somatostatin receptors were found in the peritumoral veins of 22 of 22 gastric carcinomas, 25 of 39 breast carcinomas, 15 of 20 renal cell carcinomas, 14 of 27 prostate carcinomas, 4 of 10 endometrial carcinomas, 4 of 11 pancreatic adenocarcinomas, 4 of 13 nonsmall cell lung carcinomas, as well as in 3 of 4 parathyroid adenomas, 3 of 3 medullary thyroid carcinomas, 3 of 23 gastroenteropancreatic tumors, 14 of 25 soft tissue tumors, 3 of 5 melanomas but in none (0 of 13) of the ovarian carcinomas studied. In addition, somatostatin receptors were identified in veins surrounding lymph node, bone, and lung metastases of various tumor types. In all investigated tissues, receptors could not be identified in arteries. There was a considerable variability in the relative number of veins expressing somatostatin receptors and in the receptor density levels. Evidence of an overexpression of somatostatin receptors could be established in the peritumoral veins of gastric carcinoma when compared with the receptor expression in normal gastric vessels. The expression of somatostatin receptors in peritumoral veins appears to be a general, tumor-related, but highly variable phenomenon. Although their pathophysiologic role is unclear, these receptors may be considered as novel targets for cancer diagnosis and therapy with somatostatin analogs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): July 2001
                Volume: 85
                Issue: 2
                Pages: 266-272
                Affiliations
                [1 ]Departments of Surgery, [2 ]Ophthalmology, [3 ]Radiology, [4 ]The Stanley S. Scott Cancer Center, [5 ]The Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, 70112
                [6 ]Departments of Medicine and, [7 ]Pediatrics, The Ohio State University, Columbus, Ohio, 43210
                [8 ]The Veterans Administration Medical Center, New Orleans, Louisiana, 70112, USA
                Article
                Publisher Item ID: 6691881
                DOI: 10.1054/bjoc.2001.1881
                PMC ID: 2364037
                PubMed ID: 11461088
                SO-VID: 461e3304-e23e-47a6-9a03-1c2b24d140ed
                Copyright © Copyright 2001, Cancer Research Campaign
                History
                Date received : 23 October 2000
                Date revision received : 13 March 2001
                Date accepted : 15 March 2001
                Categories
                Subject: Regular Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: vascular endothelium,gene expression,somatostatin receptors,somatostatin,receptor subtypes,angiogenesis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: vascular endothelium, gene expression, somatostatin receptors, somatostatin, receptor subtypes, angiogenesis

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