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European Journal of Nuclear Medicine Aug 1993Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization... (Review)
Review
Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.
Topics: Humans; Indium Radioisotopes; Iodine Radioisotopes; Netherlands; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin
PubMed: 8404961
DOI: 10.1007/BF00181765 -
Endocrinology May 2019The Gi-coupled somatostatin receptor 2 (SST2) is a G protein-coupled receptor (GPCR) that mediates many of somatostatin's neuroendocrine actions. Upon stimulation, SST2...
The Gi-coupled somatostatin receptor 2 (SST2) is a G protein-coupled receptor (GPCR) that mediates many of somatostatin's neuroendocrine actions. Upon stimulation, SST2 is rapidly internalized and transported to early endosomes before being recycled to the plasma membrane. However, little is known about the intracellular itinerary of SST2 after it moves to the early endosomal compartment or the cytoplasmic proteins that regulate its trafficking. As postsynaptic density protein/discs large 1/zonula occludens-1 (PDZ) domain interactions often regulate the trafficking and signaling potential of GPCRs, we examined the role of the SST2 PDZ ligand and additional C-terminal residues in controlling its intracellular trafficking. We determined that SST2 can recycle to the plasma membrane via multiple pathways, including a LAMP1/Rab7-positive late endosome to the trans-Golgi network (TGN) pathway. Trafficking from the late endosome to the TGN is often regulated by the retromer complex of endosomal coat proteins, and disrupting the retromer components sorting nexins 1/2 inhibits the budding of SST2 from late endosomes. Moreover, trafficking through the late endosomal/TGN pathway is dependent on an intact PDZ ligand and C-terminal tail, as truncating either the 3 or 10 C-terminal amino acids of SST2 alters the pathway through which it recycles to the plasma membrane. Moreover, addition of these amino acids to a heterologous receptor is sufficient to redirect it from a degradation pathway to a recycling itinerary. Our results demonstrate that endosomal trafficking of SST2 is dependent on numerous regulatory mechanisms controlled by its C terminus and the retromer machinery.
Topics: Amino Acid Motifs; Amino Acid Sequence; Base Sequence; Cell Membrane; Endosomes; HEK293 Cells; Humans; Membrane Proteins; Multiprotein Complexes; Nucleotide Motifs; PDZ Domains; Protein Transport; Receptors, Somatostatin; Signal Transduction; trans-Golgi Network
PubMed: 30822353
DOI: 10.1210/en.2018-00865 -
Molecular Oncology Feb 2022Somatostatin receptor subtype 5 (SST ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors....
Somatostatin receptor subtype 5 (SST ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Pituitary Neoplasms; Receptors, Somatostatin
PubMed: 34601790
DOI: 10.1002/1878-0261.13107 -
Trends in Pharmacological Sciences Dec 2013Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin... (Review)
Review
Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin receptor subtypes have been identified and molecular mechanisms of somatostatin receptor signaling and regulation have been elucidated. These advances increased understanding of the biological role of each somatostatin receptor subtype, their distribution in NETs, as well as agonist-specific regulation of receptor signaling, internalization, and phosphorylation, particularly for the sst2 receptor subtype, which is the primary target of current somatostatin analog therapy for NETs. Various hypotheses exist to explain differences in patient responsiveness to somatostatin analog inhibition of tumor secretion and growth as well as differences in the development of tumor resistance to therapy. In addition, we now have a better understanding of the action of both first generation (octreotide, lanreotide, Octreoscan) and second generation (pasireotide) FDA-approved somatostatin analogs, including the biased agonistic character of some agonists. The increased understanding of somatostatin receptor pharmacology provides new opportunities to design more sophisticated assays to aid the future development of somatostatin analogs with increased efficacy.
Topics: Animals; Humans; Neuroendocrine Tumors; Phosphorylation; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 24183675
DOI: 10.1016/j.tips.2013.10.001 -
Hormones (Athens, Greece) 2012
Topics: Female; Humans; Male; Receptors, Somatostatin; Thyroid Neoplasms
PubMed: 22908057
DOI: 10.1007/BF03401532 -
European Journal of Nuclear Medicine... Nov 2019To review the literature on the clinical application of radiolabeled somatostatin receptor scintigraphy (SRS) by SPECT and PET in adults with chronic inflammatory...
OBJECTIVE
To review the literature on the clinical application of radiolabeled somatostatin receptor scintigraphy (SRS) by SPECT and PET in adults with chronic inflammatory diseases.
RESEARCH DESIGN
Systematic review of published observational studies between 1993 and 2017.
DATA COLLECTION AND ANALYSIS
The Cochrane Central Register of Controlled Trials, MedLine, EMBASE, PubMed, Google Scholar, OVID, EBSCO, Scopus, and Web of Science were used to search for studies on the use of SRS in adults with chronic inflammatory diseases. A team of reviewers independently screened for eligible studies. Quality of evidence was assessed by QUADAS approach.
RESULTS
Eligible papers included 38 studies. Studied populations were heterogeneous, and patients were classified according to the diagnosed disease: endothelial inflammation, rheumatoid arthritis, cardiac allograft rejection, granulomatous diseases, small vessel vasculitis, idiopathic pulmonary fibrosis, sarcoidosis, and thyroid exophthalmopathy. Because of many quality differences between studies, it was not possible to pool data, and a narrative synthesis is reported.
CONCLUSION
Results highlight the value of SRS to detect active inflammation in several chronic inflammatory conditions, despite the bias related to the index test, showing lack of standardization of the scintigraphic technique and high variability of methods used to clinically evaluate inflammatory condition.
Topics: Chronic Disease; Humans; Inflammation; Positron-Emission Tomography; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon
PubMed: 31463594
DOI: 10.1007/s00259-019-04489-z -
International Journal of Molecular... Apr 2024Bivalves hold an important role in marine aquaculture and the identification of growth-related genes in bivalves could contribute to a better understanding of the...
Bivalves hold an important role in marine aquaculture and the identification of growth-related genes in bivalves could contribute to a better understanding of the mechanism governing their growth, which may benefit high-yielding bivalve breeding. Somatostatin receptor (SSTR) is a conserved negative regulator of growth in vertebrates. Although genes have been identified in invertebrates, their involvement in growth regulation remains unclear. Here, we identified seven s (s) in the Yesso scallop, , which is an economically important bivalve cultured in East Asia. Among the three s (, , and ) expressed in adult tissues, showed significantly lower expression in fast-growing scallops than in slow-growing scallops. Then, the function of this gene in growth regulation was evaluated in dwarf surf clams (), a potential model bivalve cultured in the lab, via RNA interference (RNAi) through feeding the clams containing plasmids expressing double-stranded RNAs (dsRNAs) targeting . Suppressing the expression of , the homolog of in , resulted in a significant increase in shell length, shell width, shell height, soft tissue weight, and muscle weight by 20%, 22%, 20%, 79%, and 92%, respectively. A transcriptome analysis indicated that the up-regulated genes after expression inhibition were significantly enriched in the fat digestion and absorption pathway and the insulin pathway. In summary, we systemically identified the s in and revealed the growth-inhibitory role of in bivalves. This study indicates the conserved function of somatostatin signaling in growth regulation, and ingesting dsRNA-expressing bacteria is a useful way to verify gene function in bivalves. is a candidate target for gene editing in bivalves to promote growth and could be used in the breeding of fast-growing bivalves.
Topics: Animals; Pectinidae; Bivalvia; Receptors, Somatostatin; Phylogeny; RNA Interference; Gene Expression Regulation, Developmental
PubMed: 38732036
DOI: 10.3390/ijms25094813 -
Journal of Neuro-oncology Sep 2023This retrospective study aimed to analyse the correlation between somatostatin receptor subtypes (SSTR 1-5) and maximum standardized uptake value (SUV) in meningioma...
OBJECTIVE
This retrospective study aimed to analyse the correlation between somatostatin receptor subtypes (SSTR 1-5) and maximum standardized uptake value (SUV) in meningioma patients using Gallium-68 DOTA-D-Phe1-Tyr3-octreotide Positron Emission Tomography ([68Ga]Ga-DOTATOC PET). Secondly, we developed a radiomic model based on apparent diffusion coefficient (ADC) maps derived from diffusion weighted magnetic resonance images (DWI MRI) to reproduce SUV.
METHOD
The study included 51 patients who underwent MRI and [68Ga]Ga-DOTATOC PET before meningioma surgery. SUV values were quantified from PET images and tumour areas were segmented on post-contrast T1-weighted MRI and mapped to ADC maps. A total of 1940 radiomic features were extracted from the tumour area on each ADC map. A random forest regression model was trained to predict SUV and the model's performance was evaluated using repeated nested cross-validation. The expression of SSTR subtypes was quantified in 18 surgical specimens and compared to SUV values.
RESULTS
The random forest regression model successfully predicted SUV values with a significant correlation observed in all 100 repeats (p < 0.05). The mean Pearson's r was 0.42 ± 0.07 SD, and the root mean square error (RMSE) was 28.46 ± 0.16. SSTR subtypes 2A, 2B, and 5 showed significant correlations with SUV values (p < 0.001, R2 = 0.669; p = 0.001, R2 = 0.393; and p = 0.012, R2 = 0.235, respectively).
CONCLUSION
SSTR subtypes 2A, 2B, and 5 correlated significantly with SUV in meningioma patients. The developed radiomic model based on ADC maps effectively reproduces SUV using [68Ga]Ga-DOTATOC PET.
Topics: Humans; Octreotide; Meningioma; Receptors, Somatostatin; Retrospective Studies; Positron-Emission Tomography; Magnetic Resonance Imaging; Meningeal Neoplasms; Organometallic Compounds
PubMed: 37707754
DOI: 10.1007/s11060-023-04414-3 -
Journal of the American College of... Jan 2023
Topics: Humans; Arteritis; Giant Cell Arteritis; Receptors, Somatostatin; Positron-Emission Tomography; Takayasu Arteritis; Fluorodeoxyglucose F18
PubMed: 36697135
DOI: 10.1016/j.jacc.2022.10.035 -
Molecular Endocrinology (Baltimore, Md.) Feb 2010Pasireotide (SOM230) is currently under clinical evaluation as a successor compound to octreotide for the treatment of acromegaly, Cushing's disease, and carcinoid...
Pasireotide (SOM230) is currently under clinical evaluation as a successor compound to octreotide for the treatment of acromegaly, Cushing's disease, and carcinoid tumors. Whereas octreotide acts primarily via the sst(2A) somatostatin receptor, pasireotide was designed to exhibit octreotide-like sst(2A) activity combined with enhanced binding to other somatostatin receptor subtypes. In the present study, we used phophosite-specific antibodies to examine agonist-induced phosphorylation of the rat sst(2A) receptor. We show that somatostatin and octreotide stimulate the complete phosphorylation of a cluster of four threonine residues within the cytoplasmic (353)TTETQRT(359) motif in a variety of cultured cell lines in vitro as well as in intact animals in vivo. This phosphorylation was mediated by G protein-coupled receptor kinases (GRK) 2 and 3 and followed by rapid cointernalization of the receptor and ss-arrestin into the same endocytic vesicles. In contrast, pasireotide failed to promote substantial phosphorylation and internalization of the rat sst(2A) receptor. In the presence of octreotide or SS-14, SOM230 showed partial agonist behavior, inhibiting phosphorylation, and internalization of sst(2A). Upon overexpression of GRK2 or GRK3, pasireotide stimulated selective phosphorylation of Thr356 and Thr359 but not of Thr353 or Thr354 within the (353)TTETQRT(359) motif. Pasireotide-mediated phosphorylation led to the formation of relatively unstable beta-arrestin-sst(2A) complexes that dissociated at or near the plasma membrane. Thus, octreotide and pasireotide are equally active in inducing classical G protein-dependent signaling via the sst(2A) somatostatin receptor. Yet, we find that they promote strikingly different patterns of sst(2A) receptor phosphorylation and, hence, stimulate functionally distinct pools of beta-arrestin.
Topics: Animals; Antibodies, Phospho-Specific; Arrestins; Cell Line; Cell Line, Tumor; Cell Membrane; Endocytosis; Humans; Ligands; Male; Octreotide; Pancreas; Phosphorylation; Pituitary Gland; Protein Isoforms; Protein Processing, Post-Translational; Rats; Rats, Wistar; Receptors, Somatostatin; Somatostatin; Threonine; beta-Adrenergic Receptor Kinases; beta-Arrestins
PubMed: 20051480
DOI: 10.1210/me.2009-0315