Growing vascular endothelial cells express somatostatin subtype 2 receptors

Watson, James C.; Balster, Douglas A.; Gebhardt, B; O’Dorisio, Thomas M.; O’Dorisio, M. Sue; Espenan, Gregory; Drouant, George J.; Woltering, Eugene A.

doi:10.1054/bjoc.2001.1881

Cited by 83 publications

(52 citation statements)

References 21 publications

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“…Previous studies have demonstrated the expression of SSTR2A and SSTR5 in fibrovascular stroma of nontumoral tissues (endothelial and immune cells) [39]; however, the expression of SSTR3 is a relative novel finding. This pattern is mainly encountered in endothelial cells of rapidly proliferating vessels and it might be correlated to neoangiogenesis [40]. …”

Section: Discussionmentioning

confidence: 99%

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Kanakis

Grimelius²,

Spathis

et al. 2015

Neuroendocrinology

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Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

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Section: Discussionmentioning

confidence: 99%

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Kanakis

Grimelius²,

Spathis

et al. 2015

Neuroendocrinology

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“…In fact, another mechanism by which SST and its analogs may exert their antiproliferative effects is the inhibition of tumor neoangiogenesis. Growing vascular endothelial cells express several SSTR subtypes (1,62), and SST regulation of tumor angiogenesis has been described in human glioma cells (43).…”

Section: Discussionmentioning

confidence: 99%

Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice

Barbieri

Pattarozzi

Gatti

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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tostatin receptors (SSTR1-5) mediate antiproliferative effects. In C6 rat glioma cells, somatostatin is cytostatic in vitro via phosphotyrosine phosphatase-dependent inhibition of ERK1/2 activity mediated by SSTR1, -2, and -5. Here we analyzed the effects of SSTR activation on C6 glioma growth in vivo and the intracellular mechanisms involved, comparing somatostatin effects with selective agonists for SSTR1, -2, and -5 (BIM-23745, BIM-23120, BIM-23206) or receptor biselective compounds (SSTR1 and -2, BIM-23704; and SSTR2 and -5, BIM-23190). Nude mice subcutaneously xenografted with C6 cells were treated with somatostatin, SSTR agonists (50 g, twice/day), or vehicle. Tumor growth was evaluated every 3 days for 19 days. The intracellular pathways responsible of SSTR effects in vivo were evaluated measuring Ki-67, phospho-ERK1/2, and p27 kip1 expression by immunohistochemistry in sections from explanted tumors. Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation and induced upregulation of p27Kip1 , whereas only a modest activation of caspase-3 was observed. Somatostatin (acting on SSTR1, -2, and -5) displayed the highest efficacy; SSTR5 selective agonist showed a stronger effect than SSTR1 agonist, and SSTR2 agonist was less effective. On the other hand, SSTR1 and -2 agonists maximally reduced tumor neovascularization. The combined activation of SSTR1 and -2 showed a synergistic activity, reaching a higher efficacy than BIM-23206, whereas the simultaneous activation of SSTR2 and -5 resulted in a response resembling SSTR5 effects. Thus the simultaneous activation of different SSTRs inhibits glioma cell proliferation in vivo through both direct cytotostatic and antiangiogenic effects. somatostatin; somatostatin receptor; glioblastoma; antiproliferative activity; in vivo; extracellular signal-regulated kinase 1/2 SOMATOSTATIN (SST), through the activation of a family of five G protein-coupled receptors [SST receptor (SSTR)1-5] (46), exerts antiproliferative effects in normal and tumor epithelial and endocrine cells (25, 51), thus providing the basis for the clinical use of SST analogs for the treatment of pituitary adenomas (13) and neuroendocrine tumors (28). SSTRs are expressed in several human cancer cells, including neuroendocrine, gastroenteropancreatic, brain, prostate, lung, and breast tumors; more than one subtype was detected in each tumor histotype, with SSTR2 the most frequently expressed subtype (54).Although both direct (induction of cell cycle arrest or apoptosis) (14) and indirect [antiendocrine (60) and antiangiogenic (2)] antitumoral activities of SST were identified, its possible clinical application as anticancer drug is still controversial (63).Multiple intracellular mechanisms Have been involved in the antiproliferative effects of SST (20). SST indirectly regulates tumor proliferation, inhibiting the release of growthpromoting hormones and growth factors (growth hormone, insulin-lik...

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“…There are several studies that support the potential anti-angiogenic effect of S Grozinsky-Glasberg et al: Somatostatin action in NETs www.endocrinology-journals.org SST and its analogues. One study hypothesised that non-proliferating human vascular endothelial cells do not express SSTR 2 but that this receptor is expressed when the endothelial cells begin to grow (Watson et al 2001); the SSTR 2 gene was expressed, and the presence of SSTR 2 on proliferating angiogenic vessels was confirmed, by immunohistochemical staining and in vivo scintigraphy, suggesting that SSTR 2 may be a specific target for anti-angiogenic therapy with SSTR 2 -binding SSAs conjugated to radioisotopes or cytotoxic agents.…”

Section: Sst's Effect On Tumour Angiogenesismentioning

confidence: 99%

Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms

Grozinsky‐Glasberg¹,

Shimon²,

Korbonits³

et al. 2008

Endocrine Related Cancer

157

119

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Neuroendocrine tumours (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), endocrine islets (within the thyroid or pancreas) as well as from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts. The development of somatostatin analogues (SSA) as important diagnostic and treatment tools has revolutionised the clinical management of patients with NETs. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with SSA, tumour regression is rare. Possible mechanisms when this does occur include antagonism of local growth factor release and effects, probably including activation of tyrosine and serine-threonine phosphatases, and indirect effects via anti-angiogenesis. The development of new SSA, new drug combination therapies and chimaeric molecules should further improve the clinical management of these patients, as should a more complete understanding of their mode of action.

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Growing vascular endothelial cells express somatostatin subtype 2 receptors

Cited by 83 publications

References 21 publications

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice

Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms

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