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Nature Reviews. Endocrinology Jul 2018The somatostatin-secreting δ-cells comprise ~5% of the cells of the pancreatic islets. The δ-cells have complex morphology and might interact with many more islet... (Comparative Study)
Comparative Study Review
The somatostatin-secreting δ-cells comprise ~5% of the cells of the pancreatic islets. The δ-cells have complex morphology and might interact with many more islet cells than suggested by their low numbers. δ-Cells contain ATP-sensitive potassium channels, which open at low levels of glucose but close when glucose is elevated. This closure initiates membrane depolarization and electrical activity and increased somatostatin secretion. Factors released by neighbouring α-cells or β-cells amplify the glucose-induced effects on somatostatin secretion from δ-cells, which act locally within the islets as paracrine or autocrine inhibitors of insulin, glucagon and somatostatin secretion. The effects of somatostatin are mediated by activation of somatostatin receptors coupled to the inhibitory G protein, which culminates in suppression of the electrical activity and exocytosis in α-cells and β-cells. Somatostatin secretion is perturbed in animal models of diabetes mellitus, which might explain the loss of appropriate hypoglycaemia-induced glucagon secretion, a defect that could be mitigated by somatostatin receptor 2 antagonists. Somatostatin antagonists or agents that suppress somatostatin secretion have been proposed as an adjunct to insulin therapy. In this Review, we summarize the cell physiology of somatostatin secretion, what might go wrong in diabetes mellitus and the therapeutic potential of agents targeting somatostatin secretion or action.
Topics: Animals; Biomarkers; Case-Control Studies; Diabetes Mellitus; Female; Glucagon; Humans; Hypoglycemia; Male; Prognosis; Receptors, Somatostatin; Reference Values; Somatostatin; Somatostatin-Secreting Cells; Treatment Outcome
PubMed: 29773871
DOI: 10.1038/s41574-018-0020-6 -
PET Clinics Apr 2023Gastro-entero-pancreatic tumors comprise a group of heterogenous neoplasms, with medical imaging being paramount in the diagnosis, staging, and treatment planning of... (Review)
Review
Gastro-entero-pancreatic tumors comprise a group of heterogenous neoplasms, with medical imaging being paramount in the diagnosis, staging, and treatment planning of these tumors. Moreover, with the advent of newer radiopharmaceuticals, such as 68 Ga-labeled and 64 Cu-labeled somatostatin analogs (eg, 68 Ga-DOTATOC, 68 Ga-DOTATATE, 68 Ga-DOTANOC, and 64Cu-DOTATATE) that bind to the somatostatin receptor (SSTR), molecular imaging plays an increasing and critical role in the diagnosis, staging, and treatment planning of these neoplasms. Dual-tracer imaging with 18F-FDG PET/CT and SSTR agents may play a significant role in treatment planning and predicting patient outcomes in the setting of high-grade or poorly differentiated neuroendocrine tumors.
Topics: Humans; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Copper Radioisotopes; Positron-Emission Tomography; Pancreatic Neoplasms; Radiopharmaceuticals; Receptors, Somatostatin; Neuroendocrine Tumors; Organometallic Compounds
PubMed: 36707371
DOI: 10.1016/j.cpet.2022.11.007 -
Current Opinion in Endocrinology,... Feb 2020Neuroendocrine tumors are heterogeneous neoplasms with variable prognoses and clinical behaviors. The majority of well differentiated NETs express somatostatin... (Review)
Review
PURPOSE OF REVIEW
Neuroendocrine tumors are heterogeneous neoplasms with variable prognoses and clinical behaviors. The majority of well differentiated NETs express somatostatin receptors. Identification of these receptors has contributed to advancements in molecular and targeted radiotherapies.
RECENT FINDINGS
Molecular scans provide important diagnostic, staging, and prognostic data. Somatostatin-receptor imaging aids in selection of patients who are eligible for somatostatin-receptor-targeting therapies. Peptide receptor radionuclide therapy has recently demonstrated robust efficacy in a phase III study of progressive midgut NETs. Current studies are investigating novel receptor agonists and antagonists, new classes of radioactive isotopes, and radiosensitizing combination treatments.
SUMMARY
The sophistication of molecular imaging is improving and its importance is increasing as a diagnostic, predictive, and prognostic tool. Theranostics, the coupling of molecular imaging with receptor-targeted therapy, represents a novel approach to cancer treatment.
Topics: Humans; Molecular Imaging; Neoplasm Staging; Neuroendocrine Tumors; Prognosis; Radioisotopes; Receptors, Somatostatin
PubMed: 31789833
DOI: 10.1097/MED.0000000000000519 -
Clinical Imaging 2019Somatostatin receptors (SSTR) are upregulated in the cells of origin that define numerous neuroendocrine neoplasms. PET imaging with Ga-DOTATATE allows specific... (Review)
Review
Somatostatin receptors (SSTR) are upregulated in the cells of origin that define numerous neuroendocrine neoplasms. PET imaging with Ga-DOTATATE allows specific targeting of SSTR2A, a single species of SSTR receptor, which is commonly overexpressed in a variety of gastroenteropancreatic neuroendocrine tumors, as well as pulmonary carcinoid and head and neck tumors. Due to more specific targeting of SSTR2 as well as lower radiation dose, shorter study length, ability to quantify uptake, and lower cost, Ga-DOTATATE has demonstrated superior imaging attributes when compared to In-pentetreotide. As with any novel imaging modality, dedicated training, increasing experience and staying up-to-date with scientific publications are required to provide optimal patient care. The purpose of this review is to summarize the current state of the art in SSTR-targeted molecular imaging and discuss ongoing and future potential diagnostic and therapeutic applications.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Molecular Imaging; Neuroendocrine Tumors; Organometallic Compounds; Positron-Emission Tomography; Receptors, Somatostatin
PubMed: 31121520
DOI: 10.1016/j.clinimag.2019.04.006 -
Progress in Molecular Biology and... 2023Somatostatin (SRIF) is a neuropeptide that acts as an important regulator of both endocrine and exocrine secretion and modulates neurotransmission in the central nervous... (Review)
Review
Somatostatin (SRIF) is a neuropeptide that acts as an important regulator of both endocrine and exocrine secretion and modulates neurotransmission in the central nervous system (CNS). SRIF also regulates cell proliferation in normal tissues and tumors. The physiological actions of SRIF are mediated by a family of five G protein-coupled receptors, called somatostatin receptor (SST) SST, SST, SST, SST, SST. These five receptors share similar molecular structure and signaling pathways but they display marked differences in their anatomical distribution, subcellular localization and intracellular trafficking. The SST subtypes are widely distributed in the CNS and peripheral nervous system, in many endocrine glands and tumors, particularly of neuroendocrine origin. In this review, we focus on the agonist-dependent internalization and recycling of the different SST subtypes in vivo in the CNS, peripheral organs and tumors. We also discuss the physiological, pathophysiological and potential therapeutic effects of the intracellular trafficking of SST subtypes.
Topics: Humans; Receptors, Somatostatin; Brain; Neoplasms
PubMed: 36813365
DOI: 10.1016/bs.pmbts.2022.09.004 -
Journal of Endocrinological... Nov 2020Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST and SST are the most represented SST subtypes. First-generation somatostatin receptor... (Review)
Review
BACKGROUND
Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST and SST are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST, while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST and SST. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors.
METHODS
Critical revision of literature data correlating SST expression with patients' response to SRLs.
RESULTS
SST expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST expression, pasireotide can act throughout SST. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST expression observed in nearly 100% of cases, as well as to the balanced amount of SST. In corticotroph tumors, pasireotide mainly act via SST, although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype.
CONCLUSIONS
The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.
Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Molecular Targeted Therapy; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 32557353
DOI: 10.1007/s40618-020-01335-0 -
Biochemical Society Transactions Feb 2021Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked... (Review)
Review
Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia provide an optimal environment for many G protein-coupled receptors (GPCRs) and their effectors to efficiently transmit their signals to the rest of the cell. For this to occur, however, all necessary receptors and signal transducers must first accumulate at the ciliary membrane. Serotonin receptor 6 (HTR6) and Somatostatin receptor 3 (SSTR3) are two GPCRs whose signaling in brain neuronal cilia affects cognition and is implicated in psychiatric, neurodegenerative, and oncologic diseases. Over a decade ago, the third intracellular loops (IC3s) of HTR6 and SSTR3 were shown to contain ciliary localization sequences (CLSs) that, when grafted onto non-ciliary GPCRs, could drive their ciliary accumulation. Nevertheless, these CLSs were dispensable for ciliary targeting of HTR6 and SSTR3, suggesting the presence of additional CLSs, which we have recently identified in their C-terminal tails. Herein, we review the discovery and mapping of these CLSs, as well as the state of the art regarding how these CLSs may orchestrate ciliary accumulation of these GPCRs by controlling when and where they interact with the ciliary entry and exit machinery via adaptors such as TULP3, RABL2 and the BBSome.
Topics: Animals; Cilia; Humans; Protein Interaction Domains and Motifs; Protein Sorting Signals; Protein Transport; Receptors, Serotonin; Receptors, Somatostatin
PubMed: 33599752
DOI: 10.1042/BST20191005 -
Expert Opinion on Pharmacotherapy Aug 2016Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for... (Review)
Review
INTRODUCTION
Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for acromegaly is targeted at decreasing GH and insulin-like growth hormone 1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant) and radiotherapy. However, despite all these treatments option, approximately 50% of patients are not adequately controlled.
AREAS COVERED
In this paper, the authors discuss: 1) efficacy and safety of current medical therapy 2) the efficacy and safety of the new multireceptor-targeted somatostatin ligand pasireotide 3) medical treatments currently under clinical investigation (oral octreotide, ITF2984, ATL1103), and 4) preliminary data on the use of new injectable and transdermal/transmucosal formulations of octreotide.
EXPERT OPINION
This expert opinion supports the need for new therapeutic agents and modalities for patients with acromegaly.
Topics: Acromegaly; Botulinum Toxins; Dopamine Agonists; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Octreotide; Oligonucleotides, Antisense; Receptors, Somatostatin; Recombinant Fusion Proteins; Somatostatin
PubMed: 27352098
DOI: 10.1080/14656566.2016.1199687 -
International Journal of Molecular... Apr 2021Somatostatin receptor subtype 4 (SST) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is...
Somatostatin receptor subtype 4 (SST) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST receptor expression and function between humans and mice, we generated an SST humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the and reporter gene construct driven by the regulatory elements were created. The vector was randomly inserted in -deficient mice. expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST humanized mouse line might enable us to investigate the differences of human and mouse SST receptor expression and function and assess the effects of SST receptor agonist drug candidates.
Topics: Animals; CA1 Region, Hippocampal; CA2 Region, Hippocampal; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Neurons; Receptors, Somatostatin
PubMed: 33916620
DOI: 10.3390/ijms22073758 -
Hellenic Journal of Nuclear Medicine 2023The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (I) labelled somatostatin...
The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (I) labelled somatostatin analogue (Krenning et al. 1989). In the years that followed an Indium-111 (In) labelled somatostatin analogue, chelated with diethylenetriaminepentaacetic acid (DTPA), was successfully developed. Subsequently, In-OctreoScan was introduced worldwide. In the years to come Tc-Tektrotyde became commercially available with easy access. In the last decade, with the increasing use of positron emission tomography (PET) imaging, somatostatin analogues have been labelled with various positron-emitting isotopes, such as Gallium-68 (Ga) and Copper-64 (Cu) (Lewis et al. 1999, Schottelius et al. 2004, Gabriel et al. 2007) e.g Ga-DOTATOC, Ga-DOTATATE Ga-DOTANOC and Cu-DOTATATE. Scintigraphy with these investigational compounds display encouraging good imaging quality amd improved sensitivity in tumor site detection compared with SPECT scintigraphy. Also, other PET radiopharmaceuticals were developed, such as F-dihydroxy-phenyl-alanine (F-DOPA) and C-labelled 5-hydroxytryptophan (C-5-HTP) with encouraging results in terms of visualization of GEP-NETs (Koopmans et al. 2008). After the successful introduction of SRS in the diagnosis and staging of NETs, the next logical step was to increase the administered activity so that the radiopharmaceutical can induce tumor shrinkage in patients who had inoperable and/or metastasized NENs. Therefore, the first peptide receptor radionuclide therapy (PRRT) was performed with high administered activity of [In-DTPA0] octreotide (Krenning et al. 1994a). To make significant advancements in the treatment of somatostatin receptor-positive metastatic disease, more efficient radiolabelled somatostatin analogues were developed with higher affinity to the somatostatin receptor. Treatment with radiolabelled peptides or PRRT is a promising new therapeutic option in the management of inoperable or metastasized NETs. Symptomatic control can be achieved with all In-, Y- and Lu-labelled somatostatin analogue-based PRRT. For objective response and long-lasting duration of response, Y-DOTATOC and Lu-DOTATATE are the most promising radiopharmaceuticals. Side effects of PRRT are few and mild, if adequate kidney protective measures are taken and dose-limits are respected. In a minority of patients, when SRS fails to identify neuroendocrine disease, MIBG scintigraphy and subsequent I-MBG therapy might be an alternative treatment option. Targeted alpha-particle therapy (TAT) has emerged as an alternative treatment option to beta emitters in PRRT. The use of alpha emitters for cancer therapy has two advantages over beta emitter PRRT. The short range of alpha particles of only a few cell diameters (<0.1mm) allows for selective ablation of the target cancer cells, while sparing the surrounding healthy tissue. In addition, the higher linear energy transfer (LET), when compared to conventional beta emitters, results in the formation of complex DNA double-strand and DNA cluster breaks, which ultimately lead to cell death.(Lassmann M et al. Ann ICRP. 2018) Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include Actinium-225 (Ac)-DOTATATE and Bismuth-213 (Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, c-DOTATATE, in the treatment of metastatic NENs. Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumors (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. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localization of the primary and metastatic disease remains the ultimate goal of research.
Topics: Humans; Radiopharmaceuticals; Receptors, Somatostatin; Gallium Radioisotopes; Iodine Radioisotopes; Copper; Somatostatin; Pancreatic Neoplasms; Neuroendocrine Tumors; DNA; Organometallic Compounds
PubMed: 37658556
DOI: No ID Found