scholarly journals Immunohistochemical Expression of Somatostatin Receptor Subtypes in a Panel of Neuroendocrine Neoplasias

2019 ◽  
Vol 67 (10) ◽  
pp. 735-743 ◽  
Author(s):  
Satu M. Remes ◽  
Helena L. Leijon ◽  
Tiina J. Vesterinen ◽  
Johanna T. Arola ◽  
Caj H. Haglund
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Membrane Receptors ◽  
Receptor Subtypes ◽  
Receptor Imaging ◽  
Primary Tumors ◽  
Somatostatin Receptor Subtypes ◽  
Negative Controls ◽  
G Protein Coupled

Neuroendocrine neoplasias (NENs) are known to express somatostatin receptors (SSTRs) 1–5, which are G-protein-coupled cell membrane receptors. Somatostatin receptor imaging and therapy utilizes the SSTR expression. Synthetic somatostatin analogs with radioligands are used to detect primary tumors, metastases, and recurrent disease. Receptor analogs are also used for treating NENs. Furthermore, commercially available SSTR antibodies can be used for the immunohistochemical (IHC) detection of SSTRs. We investigated different SSTR antibody clones applying diverse IHC protocol settings to identify reliable clones and feasible protocols for NENs. A tissue microarray including NENs from 12 different primary sites were stained. Only UMB clones were able to localize SSTR on the cell membranes of NENs. SSTR2 (UMB1) emerged as the most common subtype followed by SSTR5 (UMB4) and SSTR1 (UMB7). SSTR3 (UMB5) expression was mainly cytoplasmic. Yet, SSTR4 expression was weak and located primarily in the cytoplasm. Thus, appropriate IHC protocols, including proper positive and negative controls, represent requirements for high-quality NEN diagnostics and for planning personalized therapy.

Novel insights in somatostatin receptor physiology

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S3-S11 ◽  
Author(s):  
Giovanni Tulipano ◽  
Stefan Schulz
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Receptor Subtypes ◽  
Ligand Complex ◽  
Endosomal Sorting ◽  
Intracellular Vesicle ◽  
Molecular Events ◽  
Somatostatin Receptor Subtypes

The experimental data reviewed in the present paper deal with the molecular events underlying the agonist-dependent regulation of the distinct somatostatin receptor subtypes and may suggest important clues about the clinical use of somatostatin analogs with different pattern of receptor specificity for the in vivo targeting of tumoral somatostatin receptors. Somatostatin receptor subtypes are characterized by differential β-arrestin trafficking and endosomal sorting upon agonist binding due, at least in part, to the differences in their C-terminal tails. Moreover, the subcellular expression pattern of somatostatin receptor subtypes and their activity in response to agonist treatment are affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking. Different somatostatin analogs may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signaling or receptor endocytosis.

scholarly journals Somatostatin receptor expression in parathyroid neoplasms

2019 ◽  
Vol 8 (8) ◽  
pp. 1213-1223 ◽  
Author(s):  
Sara Storvall ◽  
Helena Leijon ◽  
Eeva Ryhänen ◽  
Johanna Louhimo ◽  
Caj Haglund ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Parathyroid Carcinoma ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Expression ◽  
Benign Tumors ◽  
Receptor Subtypes ◽  
Receptor Imaging ◽  
Somatostatin Receptor Subtypes ◽  
Parathyroid Adenomas

Introduction Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown. Aim Our aim is to examine the immunohistochemical expression of somatostatin receptor 1–5 in parathyroid typical adenomas, atypical adenomas and carcinomas. Methods We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1–5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics. Results All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression. Conclusions Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1–5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.

scholarly journals Evaluation of a New 177Lu-Labeled Somatostatin Analog for the Treatment of Tumors Expressing Somatostatin Receptor Subtypes 2 and 5

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4155
Author(s):  
Rosalba Mansi ◽  
Guillaume Pierre Nicolas ◽  
Luigi Del Pozzo ◽  
Karim Alexandre Abid ◽  
Eric Grouzmann ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Somatostatin Analog ◽  
Receptor Subtypes ◽  
In Vivo Evaluation ◽  
Somatostatin Receptor Subtypes ◽  
Lower Extent ◽  
Lower Background

Targeted radionuclide therapy of somatostatin receptor (SST)-expressing tumors is only partially addressed by the established somatostatin analogs having an affinity for the SST subtype 2 (SST2). Aiming to target a broader spectrum of tumors, we evaluated the bis-iodo-substituted somatostatin analog ST8950 ((4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2), having subnanomolar affinity for SST2 and SST5, labeled with [177Lu]Lu3+ via the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Human Embryonic Kidney (HEK) cells stably transfected with the human SST2 (HEK-SST2) and SST5 (HEK-SST5) were used for in vitro and in vivo evaluation on a dual SST2- and SST5-expressing xenografted mouse model. natLu-DOTA-ST8950 showed nanomolar affinity for both subtypes (IC50 (95% confidence interval): 0.37 (0.22–0.65) nM for SST2 and 3.4 (2.3–5.2) for SST5). The biodistribution of [177Lu]Lu-DOTA-ST8950 was influenced by the injected mass, with 100 pmol demonstrating lower background activity than 10 pmol. [177Lu]Lu-DOTA-ST8950 reached its maximal uptake on SST2- and SST5-tumors at 1 h p.i. (14.17 ± 1.78 and 1.78 ± 0.35%IA/g, respectively), remaining unchanged 4 h p.i., with a mean residence time of 8.6 and 0.79 h, respectively. Overall, [177Lu]Lu-DOTA-ST8950 targets SST2-, SST5-expressing tumors in vivo to a lower extent, and has an effective dose similar to clinically used radiolabeled somatostatin analogs. Its main drawbacks are the low uptake in SST5-tumors and the persistent kidney uptake.

Prognostic role of somatostatin receptor subtypes in human prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16120-e16120
Author(s):  
A. Gernone ◽  
V. Pagliarulo ◽  
S. Trabucco
Keyword(s):  
Prostate Cancer ◽  
Single Cells ◽  
Performance Status ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Neuroendocrine Differentiation ◽  
Patient Characteristics ◽  
Receptor Subtypes ◽  
Ecog Performance Status ◽  
Somatostatin Receptor Subtypes

e16120 Background: Neuroendocrine differentiation (NED) in prostate carcinoma (PC) is frequently detected by immunohistochemistry as single cells in conventional adenocarcinoma. NED of PC correlates with poor prognosis and tumor progression during androgen-deprivation therapy. The aim of our study was to correlate the expression of somatostatin receptor (SSTR) 1, 2, 3, 4, 5 subtypes in primary PC with NED pattern and Overall Survival (OS). Methods. PC tissues were reviewed from 100 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2002 to 2007. 24 samples expressed hystologically chromogranin A (CgA), a marker of NED expression. Patient characteristics included: median age 68 years (range 45–83), median baseline PSA: 70 ng/ml (range 0.3–200), median ECOG Performance Status: 1 (range 0–2), Gleason score ≥ 7, medium serum level of CgA was 56.2 nmol/L (range 0.5–120). Results: The expression of SSTR subtypes (1, 2, 3, 4, 5) were investigated and our data identified four histological features. SSTR1 was expressed in 4/24 samples, SSTR 5 was detected in 2/24 samples, both SSTR1 and SSTR5 were found in 6/24 samples. OS at last follow up on July 2008 was 60%. SSTR 1–5 were undetectable in 12/24 pts with more aggressive clinical course and the OS was < 10%. The PSA and CgA levels were not correlated with clinical outcome. SSTR subtypes 2, 3 an 4 were not expressed in all 24 samples. Conclusions: SSTRs expression significantly correlated with OS. The absence of SSTR 1 and 5 in more aggressive disease could represent a growth advantage in NED prostate cancer. SSTRs and somatostatin analogs are potential targets for prostate cancer treatment. No significant financial relationships to disclose.

Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours

2011 ◽  
Vol 18 (S1) ◽  
pp. S27-S51 ◽  
Author(s):  
Jaap J M Teunissen ◽  
Dik J Kwekkeboom ◽  
R Valkema ◽  
Eric P Krenning
Keyword(s):  
Nuclear Medicine ◽  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Somatostatin Analogues ◽  
Imaging Modalities ◽  
Tumour Regression ◽  
Receptor Subtypes ◽  
Receptor Imaging ◽  
Imaging Method ◽  
Somatostatin Receptor Subtypes

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [177Lu-DOTA0,Tyr3]octreotate, a survival benefit of several years compared with historical controls has been reported.

scholarly journals Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts

2005 ◽  
Vol 187 (3) ◽  
pp. 379-386 ◽  
Author(s):  
William H T Smith ◽  
R Unnikrishnan Nair ◽  
Dawn Adamson ◽  
Mark T Kearney ◽  
Stephen G Ball ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Human Heart ◽  
Cardiac Fibroblasts ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Cell Types ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Somatostatin Receptor Subtypes ◽  
Human Cardiac Fibroblasts

In acromegaly, somatostatin receptor ligands (SRLs) can ameliorate left ventricular hypertrophy (LVH) and their use is associated with demonstrable improvements in various parameters of cardiac function. It remains unclear as to whether these beneficial effects are principally attributable to falling GH and IGF-I levels, or whether SRLs exert independent direct effects on the heart via somatostatin receptors. To help address this issue, we have sought to investigate somatostatin receptor expression in human heart. A human heart cDNA library was probed using PCR techniques to determine expression of somatostatin receptor subtypes. Subsequently, human heart biopsies and human cardiac fibroblasts and myocytes were analysed to determine whether expression differed between cardiac chambers or cell types. mRNAs for four of the five somatostatin receptor subtypes (sst1, sst2, sst4 and sst5) were shown to be co-expressed by the human heart. These receptors were present in both atrial and ventricular tissue. Human cardiac myocytes expressed mRNA for only sst1 and sst2, while human cardiac fibroblasts expressed all four subtypes found in whole heart tissue. The expression of functional somatostatin receptors on human cardiac fibroblasts was confirmed by mobilisation of intracellular calcium in response to somatostatin. The presence of cardiac somatostatin receptors raises the possibility of a direct effect of somatostatin analogues on the heart. Furthermore, the differential expression of somatostatin receptor subtypes by human cardiac myocytes and fibroblasts opens up the possibility of differential modulation of the cell types in the heart by subtype-specific somatostatin analogues.

scholarly journals Localization of Neuroendrocrine Tumors Using Somatostatin Receptor Imaging with Indium-111-Pentetreotide (OctreoScan)

1997 ◽  
Vol 4 (1) ◽  
pp. 1-3 ◽  
Author(s):  
E. Christopher Ellison ◽  
William J. Schirmer ◽  
John O. Olsen ◽  
Rodney V. Pozderac ◽  
George Hinkle ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Imaging Techniques ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Imaging ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Primary Tumors ◽  
Duodenal Tumor ◽  
Computed Tomography Scanning ◽  
Indium 111

Background Many imaging methods have been used to detect neuroendocrine tumors of the gastrointestinal system. There is no gold standard for identifying the location of primary tumors and their potential metastases, and most conventional imaging techniques cannot detect tumors less than 1.0 cm in size. Methods The authors have investigated the use of 111In-pentetreotide as an imaging agent for abdominal neuroendocrine tumors. Results The agent is cleared rapidly by the kidneys and is primarily excreted intact with a biologic half-life of six hours. The largest radiation burden is to the spleen and kidneys. A nine-center study conducted in Europe involved 365 patients with gastroenteropancreatic neuroendocrine tumors that were also imaged by other methods. The results of 111In-pentetreotide were in agreement with those obtained by other methods for 79% of tumor locations. An additional 110 tumor localizations were detected that were not seen with conventional methods. The smallest gastrinoma imaged by 111In-pentetreotide was a 4-mm duodenal tumor. Conclusions Scintigraphy with 111In-pentetreotide is effective in visualizing various somatostatin receptors characteristic of neuroendocrine tumors of the gastrointestinal tract. Insulinomas, however, are not well imaged. Concurrent computed tomography scanning is advised to minimize the risk of missing liver metastases.

scholarly journals Somatostatin receptor subtypes 1 and 4 redundantly regulate neprilysin, the major amyloid-beta degrading enzyme in brain

2020 ◽  
Author(s):  
Per Nilsson ◽  
Karin Sörgjerd ◽  
Naomasa Kakiya ◽  
Hiroki Sasaguri ◽  
Naoto Watamura ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amyloid Beta ◽  
Molecular Layer ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Subtypes ◽  
Double Knockout ◽  
Degrading Enzyme ◽  
Somatostatin Receptor Subtypes ◽  
Ad Mouse Model

Alzheimer’s disease (AD) brains are characterized by increased levels of the pathogenic amyloid beta (Aβ) peptide, which accumulates into extracellular plaques. Finding a way to lower Aβ levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aβ degrading enzyme which is regulated by the neuropeptide somatostatin. Here we used a combination of in vitro and in vivo approaches to identify the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin. Using a battery of Sst double knockout (dKO) mice we show that neprilysin is regulated by SST1 and SST4 in a redundant manner. Sst1 and Sst4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst1 and Sst4 in amyloid beta precursor protein (App) knock-in mice, an AD mouse model, aggravates the Aβ pathology in the hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an agonist selective for SST1 and SST4 ameliorates the Aβ pathology and improves cognition in the App knock-in AD mouse model.

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