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Biochimica Et Biophysica Acta Sep 2003In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and... (Review)
Review
In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced that a neuropeptide, to be named cortistatin (CST), had been cloned, bearing strong resemblance to SRIF. Evidence of special CST receptors never emerged, however. CST rather competed with both SRIF isoforms for specific receptor binding. And binding to the known subtypes with affinities in the nanomolar range, it has therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing the characteristic seven-transmembrane-segment (STMS) topography. Years of intensive research have resulted in cloning of five receptor subtypes (sst(1)-sst(5)), one of which is represented by two splice variants (sst(2A) and sst(2B)). The individual subtypes, functionally coupled to the effectors of signal transduction, are differentially expressed throughout the mammalian organism, with corresponding differences in physiological impact. It is evident that receptor function, from a physiological point of view, cannot simply be reduced to the accumulated operations of individual receptors. Far from being isolated functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual receptor subtypes are highly cell-specific and vary with the co-expression of different-ligand receptors. However, the question is how to quantify the relative contributions of individual receptor subtypes to the integration of transduced signals, ultimately the result of collective receptor activity. The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype-selective analogues. Several have become available.
Topics: Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Protein Conformation; Protein Subunits; Receptors, Somatostatin; Signal Transduction; Structure-Activity Relationship
PubMed: 14507421
DOI: 10.1016/s0005-2736(03)00235-9 -
Postepy Biochemii Oct 2018Somatostatin is a peptide that participates in numerous biochemical and signaling pathways. It functions via receptors (SSTRs1-5), which belong to the family of... (Review)
Review
Somatostatin is a peptide that participates in numerous biochemical and signaling pathways. It functions via receptors (SSTRs1-5), which belong to the family of receptors coupled with protein G. All somatostatin receptors are characterized by a certain degree of homology in molecular structure. The cell effects of their agonists in peripheral tissues rely mainly on the inhibition of the hormones release. Somatostatin is also an important neuromodulator and neurotransmitter. SSTRs may affect other receptors, forming structural and functional homodimers and heterodimers. SSTRs play also role in the regulation of physiological processes, such as itching and pain, reproductive functions, regulation of feeding or mood. Besides physiological functions, SSTRs contribute also to the pathogenesis of glial tumors, neurodegenerative diseases, or post hemorrhagic stroke changes. Recent years of research have provided new data regarding the role of somatostatin receptor signaling pathways in the brain and the knowledge in this field is developing rapidly.
Topics: Brain; Humans; Neurotransmitter Agents; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 30656906
DOI: 10.18388/pb.2018_133 -
Journal of Cellular and Molecular... Nov 2010Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs... (Review)
Review
Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.
Topics: Humans; Neuroendocrine Tumors; Pituitary Neoplasms; Receptors, Somatostatin; Signal Transduction
PubMed: 20629989
DOI: 10.1111/j.1582-4934.2010.01125.x -
Journal of Nuclear Medicine : Official... Oct 2021A new era of precision diagnostics and therapy for patients with neuroendocrine neoplasms began with the approval of somatostatin receptor (SSTR) radiopharmaceuticals...
A new era of precision diagnostics and therapy for patients with neuroendocrine neoplasms began with the approval of somatostatin receptor (SSTR) radiopharmaceuticals for PET imaging followed by peptide receptor radionuclide therapy (PRRT). With the transition from SSTR-based γ-scintigraphy to PET, the higher sensitivity of the latter raised questions regarding the direct application of the planar scintigraphy-based Krenning score for PRRT eligibility. Also, to date, the role of SSTR PET in response assessment and predicting outcome remains under evaluation. In this comprehensive review article, we discuss the current role of SSTR PET in all aspects of neuroendocrine neoplasms, including its relation to conventional imaging, selection of patients for PRRT, and the current understanding of SSTR PET-based response assessment. We also provide a standardized reporting template for SSTR PET with a brief discussion.
Topics: Neuroendocrine Tumors; Positron-Emission Tomography; Precision Medicine; Receptors, Somatostatin
PubMed: 34301785
DOI: 10.2967/jnumed.120.251512 -
BioMed Research International 2013Neuroendocrine tumors (NETs) are tumors originated from neuroendocrine cells in the body. The localization and the detection of the extent of NETs are important for... (Review)
Review
Neuroendocrine tumors (NETs) are tumors originated from neuroendocrine cells in the body. The localization and the detection of the extent of NETs are important for diagnosis and treatment, which should be individualized according to the tumor type, burden, and symptoms. Molecular imaging of NETs with high sensitivity and specificity is achieved by nuclear medicine method using single photon-emitting and positron-emitting radiopharmaceuticals. Somatostatin receptor imaging (SRI) using SPECT or PET as a whole-body imaging technique has become a crucial part of the management of NETs. The radiotherapy with somatostatin analogues labeled with therapeutic beta emitters, such as lutetium-177 or yttrium-90, has been proved to be an option of therapy for patients with unresectable and metastasized NETs. Molecular imaging can deliver an important message to improve the outcome for patients with NETs by earlier diagnosis, better choice of the therapeutic method, and evaluation of the therapeutic response.
Topics: Humans; Lutetium; Molecular Imaging; Neuroendocrine Tumors; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Yttrium Radioisotopes
PubMed: 24106690
DOI: 10.1155/2013/102819 -
Current Oncology Reports Nov 2021Accurate imaging is crucial for correct diagnosis, staging, and therapy of neuroendocrine neoplasms (NENs). The search for the optimal imaging technique has triggered... (Review)
Review
PURPOSE OF REVIEW
Accurate imaging is crucial for correct diagnosis, staging, and therapy of neuroendocrine neoplasms (NENs). The search for the optimal imaging technique has triggered rapid development in the field. This review aims at giving an overview on contemporary imaging methods and providing an outlook on current progresses.
RECENT FINDINGS
The discovery of molecular targets due to the overexpression of specific peptide hormone receptors on the NEN's surface has triggered the development of multiple radionuclide imaging modalities. In addition to the established imaging technique of targeting somatostatin receptors, several alternative radioligands have been developed. Targeting the glucagon-like peptide-1 receptor by exendin-4 has a high sensitivity in localizing insulinomas. For dedifferentiated NENs, new molecular targets such as the C-X-C motif chemokine-receptor-4 have been evaluated. Other new targets involve the fibroblast activation protein and the cholecystokinin-2 receptors, where the ligand minigastrin opens new possibilities for the management of medullary thyroid carcinoma. Molecular imaging is an emerging field that improves the management of NENs.
Topics: Humans; Neuroendocrine Tumors; Peptides; Radionuclide Imaging; Receptors, Cholecystokinin; Receptors, Somatostatin
PubMed: 34735669
DOI: 10.1007/s11912-021-01139-2 -
Nuclear Medicine Review. Central &... 2016The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in... (Review)
Review
The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in clinical routine or in early phase clinical trials. Somatostatin (sst) receptor targeting with radiolabeled peptides has become an integral part in nuclear oncology during the last 20 years. This integration process has been initiated in Europe with the introduction to the market of 111In-DTPA-DPhe1-octreotide [111In-pentetreotide]. Introducing 99mTc in somatostatin receptor targeting radiopeptides resulted in much better image quality, higher sensitivity of tumor detection and lower mean effective dose for the examined patient. The next generation are 68Ga labeled somatostatin analogs. Due to the spatial resolution of PET technique and increasing number of PET scanners, the PET or PET/CT technique became very important in somatostatin receptor imaging. Until up to a couple of years ago the analogs of somatostatin were constructed aiming at their agonistic behavior, expecting that their internalization with the receptor acti-vated by the radiolabeled ligand and its retention within the tumor cell are crucial for efficient imaging and therapy. Recently it has been shown that the antagonists recognize more binding sites at the tumor cell membrane and hence offer an improved diagnostic efficacy, especially when the density of sst receptors is low. This approach may in future improve diagnostic value of somatostatin receptor imaging techniques. The developments in tracer design are followed by the improvements in imaging techniques. The new SPECT scanners offer resolution close to that of PET, which might open a new era for 99mTc and other SPECT radiotracers.
Topics: Drug Stability; Humans; Molecular Imaging; Neuroendocrine Tumors; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin
PubMed: 27479790
DOI: 10.5603/NMR.2016.0024 -
Frontiers in Endocrinology 2022The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs),... (Review)
Review
The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs), and medullary thyroid cancers (MTCs) are limited. While there are several systemic targeted therapies, such as tyrosine kinase inhibitors, that are being evaluated and implemented in the treatment of these cancers, such therapies are associated with serious, sometimes life-threatening, adverse events. Peptide receptor radionuclide therapy (PRRT) has the potential to be an effective and safe modality for treating patients with somatostatin receptor (SSTR)+ RAI-refractory DTCs and MTCs. MTCs and certain sub-types of RAI-refractory DTCs, such as Hürthle cell cancers which are less responsive to conventional modalities of treatment, have demonstrated a favorable response to treatment with PRRT. While the current literature offers hope for utilization of PRRT in thyroid cancer, several areas of this field remain to be investigated further, especially head-to-head comparisons with other systemic targeted therapies. In this review, we provide a comprehensive outlook on the current translational and clinical data on the use of various PRRTs, including diagnostic utility of somatostatin analogs, theranostic properties of PRRT, and the potential areas for future research.
Topics: Carcinoma, Neuroendocrine; Humans; Iodine Radioisotopes; Receptors, Somatostatin; Thyroid Neoplasms
PubMed: 35712243
DOI: 10.3389/fendo.2022.896287 -
Hormones and Behavior Jul 2015Somatostatin was discovered four decades ago as hypothalamic factor inhibiting growth hormone release. Subsequently, somatostatin was found to be widely distributed... (Review)
Review
Somatostatin was discovered four decades ago as hypothalamic factor inhibiting growth hormone release. Subsequently, somatostatin was found to be widely distributed throughout the brain and to exert pleiotropic actions via interaction with five somatostatin receptors (sst1-5) that are also widely expressed throughout the brain. Interestingly, in contrast to the predominantly inhibitory actions of peripheral somatostatin, the activation of brain sst2 signaling by intracerebroventricular injection of stable somatostatin agonists potently stimulates food intake and independently, drinking behavior in rodents. The orexigenic response involves downstream orexin-1, neuropeptide Y1 and μ receptor signaling while the dipsogenic effect is mediated through the activation of the brain angiotensin 1 receptor. Brain sst2 activation is part of mechanisms underlying the stimulation of feeding and more prominently water intake in the dark phase and is able to counteract the anorexic response to visceral stressors.
Topics: Animals; Appetite Regulation; Brain; Drinking; Drinking Behavior; Eating; Feeding Behavior; Humans; Receptors, Somatostatin; Rodentia; Somatostatin
PubMed: 26026616
DOI: 10.1016/j.yhbeh.2015.05.009 -
International Journal of Molecular... Jan 2022Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and... (Review)
Review
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA-mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
Topics: Humans; Neoplasm Metastasis; Neuroendocrine Tumors; Prognosis; Receptors, Somatostatin; Signal Transduction; Somatostatin; Survival Rate
PubMed: 35163374
DOI: 10.3390/ijms23031447