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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 -
Trends in Endocrinology and Metabolism:... Mar 2010Somatotropin-release inhibitory factor (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell... (Review)
Review
Somatotropin-release inhibitory factor (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell growth. Five SRIF receptor subtypes (SSTR1-5) are ubiquitously expressed G-protein coupled receptors. In the pituitary, SSTR1, 2, 3 and 5 are expressed, with SSTR2 and SSTR5 predominating. As new SRIF analogs have recently been introduced for treatment of pituitary disease, we evaluate the current knowledge of cell-specific pituitary SRIF receptor signaling and highlight areas of future research for comprehensive understanding of these mechanisms. Elucidating pituitary SRIF receptor signaling enables understanding of pituitary hormone secretion and cell growth, and also encourages future therapeutic development for pituitary disorders.
Topics: Animals; Humans; Models, Biological; Pituitary Diseases; Pituitary Hormones; Receptors, Somatostatin; Signal Transduction
PubMed: 20149677
DOI: 10.1016/j.tem.2009.12.003 -
Frontiers in Endocrinology 2021Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells,... (Review)
Review
Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells, and the inhibitory function of somatostatin-containing cells is involved in a range of physiological functions and pathological modifications. The GI system is the largest endocrine organ for digestion and absorption, SST-endocrine cells and neurons in the GI system are a critical effecter to maintain homeostasis SSTRs 1-5 and co-receptors, while SST-SSTRs are involved in chemo-sensory, mucus, and hormone secretion, motility, inflammation response, itch, and pain the autocrine, paracrine, endocrine, and exoendocrine pathways. It is also a power inhibitor for tumor cell proliferation, severe inflammation, and post-operation complications, and is a first-line anti-cancer drug in clinical practice. This mini review focuses on the current function of producing SST endocrine cells and local neurons SST-SSTRs in the GI system, discusses new development prognostic markers, phosphate-specific antibodies, and molecular imaging emerging in diagnostics and therapy, and summarizes the mechanism of the SST family in basic research and clinical practice. Understanding of endocrines and neuroendocrines in SST-SSTRs in GI will provide an insight into advanced medicine in basic and clinical research.
Topics: Animals; Antineoplastic Agents; Cell Communication; Cell Proliferation; Disease Models, Animal; Enteric Nervous System; Gastrointestinal Tract; Homeostasis; Humans; Inflammation; Ligands; Neurons; Parasympathetic Nervous System; Prognosis; Receptors, Somatostatin; Somatostatin; Somatostatin-Secreting Cells; Sympathetic Nervous System
PubMed: 33796080
DOI: 10.3389/fendo.2021.652363 -
Molecular and Cellular Endocrinology May 2008The five somatostatin receptor subtypes, named sst1-sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation.... (Review)
Review
The five somatostatin receptor subtypes, named sst1-sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation. Until recently it was believed that once a particular somatostatin receptor was activated by an agonist, all the down-stream signaling and regulatory effects characteristic of that receptor subtype in that cellular environment would be triggered. Thus, differences in the actions of somatostatin analogs between tissues were attributed to variability in the nature and concentration of the sst receptor subtypes and effectors expressed in different targets. However, agonists have recently been shown to exhibit functional selectivity at individual sst receptors such that they can elicit a subset of that receptor's potential effects, a property known as biased agonism. This review will summarize the evidence for functionally selective somatostatin receptor agonists and discuss the implications and promise of these new findings.
Topics: Animals; Humans; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 18006219
DOI: 10.1016/j.mce.2007.09.009 -
Human Pathology Nov 2021Viruses are known drivers of head and neck squamous cell carcinomas (HNSCC), particularly Epstein-Barr virus (EBV) and human papillomavirus (HPV). Both EBV-positive...
Viruses are known drivers of head and neck squamous cell carcinomas (HNSCC), particularly Epstein-Barr virus (EBV) and human papillomavirus (HPV). Both EBV-positive nasopharyngeal carcinoma (EBVNPC) and HPV-positive oropharyngeal SCC (OPSCC) can have overlapping histomorphology and molecular signatures, including nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) pathway mutations. A recent study showed that NFKB activation in EBVNPC drives somatostatin receptor 2 (SSTR2) expression that is detectable by immunohistochemistry and by imaging with 68-Gadolinium-DOTA-peptide radioconjugate. However, whether a similar NFKB-SSTR2 signaling mechanism exists for other virus-positive HNSCC, namely HPV-positive sinonasal carcinomas and OPSCC, remains unclear. Here we examined SSTR2 expression in a cohort of EBV-positive, HPV-positive, and virus-negative HNSCC with immunohistochemistry. SSTR2 immunohistochemistry was performed on our cohort of primary and/or metastatic EBVNPC, HPV-positive sinonasal SCC, OPSCC, HPV-negative sinonasal and oral cavity SCC, and benign tonsil and adenoid tissue. For SSTR2 staining, the extent was categorized as focal, multifocal, or diffuse, and the intensity was categorized as weak, moderate, or strong. Multifocal/diffuse SSTR2 staining of any intensity was considered positive. Among primary, recurrent, and/or undifferentiated NPC, 90% showed multifocal to diffuse strong SSTR2 expression. One HPV-positive sinonasal carcinoma showed patchy SSTR2 staining. None of the remaining HPV-positive sinonasal carcinomas, OPSCC, or oral cavity HNSCC showed significant SSTR2 staining. Overall, SSTR2 is highly sensitive and specific for EBVNPC and could represent a surrogate biomarker. Among HNSCC assessed here, we recommend testing primary NPC for SSTR2 because of its relevance for diagnosis, associated imaging modalities, and its therapeutic implications for patient care.
Topics: Adult; Aged; Biomarkers, Tumor; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Receptors, Somatostatin; Sensitivity and Specificity
PubMed: 34416258
DOI: 10.1016/j.humpath.2021.08.004 -
Endocrine Reviews Feb 2003Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine... (Review)
Review
Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-positive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed.
Topics: Animals; Drug Resistance; Gene Expression; Humans; Neoplasms; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Tachyphylaxis
PubMed: 12588807
DOI: 10.1210/er.2000-0001 -
Frontiers in Endocrinology 2022Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and... (Review)
Review
Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of β- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI.
Topics: Biology; Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; Ligands; Receptors, Somatostatin; Somatostatin
PubMed: 36237195
DOI: 10.3389/fendo.2022.921357 -
Journal of Internal Medicine Jun 1998Somatostatin receptors are expressed on the majority of neuroendocrine tumours. The presence of these receptors is clinically useful. First, long-term treatment with... (Review)
Review
Somatostatin receptors are expressed on the majority of neuroendocrine tumours. The presence of these receptors is clinically useful. First, long-term treatment with somatostatin analogues controls hormonal hypersecretion, which controls flushing attacks, watery diarrhoea, hypoglycaemia and electrolyte disorders in patients with carcinoids and islet cell tumours. Secondly, somatostatin receptor imaging is used to localize primary neuroendocrine tumours and to visualize the spread of the disease. Thirdly internalization of somatostatin receptors by primary neuroendocrine tumours opens the possibility of carrying out radio- and chemotherapy with somatostatin analogues coupled to beta-emitting radionuclides and chemotherapeutic drugs. The presence and role of somatostatin receptors on the tumours which occur in multiple endocrine neoplasia and von Hippel-Lindau disease are discussed.
Topics: Gene Expression Regulation, Neoplastic; Humans; Multiple Endocrine Neoplasia; Receptors, Somatostatin; von Hippel-Lindau Disease
PubMed: 9681860
DOI: 10.1046/j.1365-2796.1998.00340.x -
Islets Dec 2023Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated...
Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically encoded beta cell-specific GCaMP6f calcium reporter shows that somatostatin signaling alters beta cell calcium flux after physiologic glucose stimulation, an effect that depends on endogenous SSTR3 expression and the presence of intact primary cilia on beta cells. Comparative studies using SSTR isoform antagonists demonstrate a role for SSTR3 in mediating somatostatin regulation of insulin secretion in mouse islets. Our findings support a model in which ciliary SSTR3 mediates a distinct pathway of delta-to-beta cell regulatory crosstalk and may serve as a target for paracrine modulation.
Topics: Cilia; Glucose; Receptors, Somatostatin; Somatostatin; Animals; Mice
PubMed: 37660302
DOI: 10.1080/19382014.2023.2252855 -
International Journal of Molecular... Aug 2022Acromegaly is a chronic and systemic disease due to excessive growth hormone and insulin-like growth factor type I caused, in the vast majority of cases, by a... (Review)
Review
Acromegaly is a chronic and systemic disease due to excessive growth hormone and insulin-like growth factor type I caused, in the vast majority of cases, by a GH-secreting pituitary adenoma. About 40% of these tumors have somatic mutations in the stimulatory G protein alpha-subunit 1 gene. The pathogenesis of the remaining tumors, however, is still not fully comprehended. Surgery is the first-line therapy for these tumors, and first-generation somatostatin receptor ligands (fg-SRL) are the most prescribed medications in patients who are not cured by surgery. MicroRNAs are small, non-coding RNAs that control the translation of many mRNAs, and are involved in the post-transcriptional regulation of gene expression. Differentially expressed miRNAs can explain differences in the pathogenesis of acromegaly and tumor resistance. In this review, we focus on the most validated miRNAs, which are mainly involved in acromegaly’s tumorigenesis and fg-SRL resistance, as well as in circulating miRNAs in acromegaly.
Topics: Acromegaly; Adenoma; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; MicroRNAs; Receptors, Somatostatin; Somatostatin
PubMed: 35955787
DOI: 10.3390/ijms23158653