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Due to the unique optical properties like high brightness and narrow emission bands of Quantum dots, it is used as simple fluorescence materials in bio-imaging, immunoassays, microarrays, and other applications. To easy invistigate cell lines that overexpressed somtostatin receptors, somatostatin (SST) was conjugated with Quantum dots carrying PEG amine (Qdots-PEG-NH2). The conjugation of SST to Qdots-PEG-NH2 started with the thiolation of SST using Traut's reagent. Moreover, the Qdots-PEG-NH2 were subsequently activated by 500-fold molar excess of sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) dissolved in phosphate buffer. The Qdots-PEG-NH2-sulfo-SMCC was conjugated to the thiolated-SST to form Qdots-SST. The number of sulfhydryl groups can be controlled by the molar ratio of Traut´s reagent to SST. Thiolation was necessary for the conjugation of SST to Qdots-PEG-NH2. This was achieved by reacting the SST with Traut's reagent in a 1:1 molar ratio. Ellman's reagent was used to determine the number of sulfhydryle groups. Furthermore, cellular uptake study on triple negative breast cancer cells (HCC-1806) showed that the numbers of Qdots-SST per cell were significantly higher compared to unmodified Qdots-PEG-NH2 when quantified using inductively coupled plasma optical emission spectroscopy (ICP-OES). Moreover, the binding of Qdots-SST to cells can be suppressed by addition of free SST, indicating that the binding of Qdots-SST to cells is due to receptor-specific binding.
Meningiomas have high recurrence rates despite frequently benign histopathological appearances. Somatostatin receptors (SSTRs) may be reliable biomarkers that could identify patients with increased risk of recurrence. Even though SSTRs are previously detected in meningiomas, their associations to clinicopathological features remain unclear. The aim of this study was to investigate the diagnostic and prognostic value of SSTRs in a large series of human meningiomas with long follow-up data. Immunohistochemistry was used to measure the expression of SSTR1-SSTR5 in tissue samples from 162 patients diagnosed with intracranial meningiomas of World Health Organization (WHO) grade 1 or 2. Digital scoring and a manual staining index were applied to assess immunoreactivity. All SSTRs, except SSTR4, were upregulated in our series of meningiomas. SSTR1 (p = 0.036), SSTR2 (p = 0.036) and SSTR5 (p = 0.029) were associated with a higher malignancy grade. SSTR2 presented as the most reliable marker. Only SSTR2 was associated with time to recurrence (TTR) in univariate Cox regression analyses. Manual staining index was strongly correlated with digital scoring for all SSTRs (r > 0.65, p < 0.001). SSTRs, and especially SSTR2, are useful in the diagnostics of meningiomas, even though their prognostic value appears limited. Digital scoring is valuable to ensure reproducibility.
1. We have used somatostatin (SRIF) receptor subtype-selective ligands to determine some of the operational characteristics of somatostatin receptors in Neuro2A mouse neuroblastoma cells. The potent SRIF1-receptor selective ligand, BIM-23027, was able to displace completely the specific binding of radioiodinated somatostatin, [125I]-Tyr11-SRIF-14, with a pIC50 of 10.3, suggesting that Neuro2A cells contain predominantly receptors of the SRIF1 receptor group. The rank order of affinities for several somatostatin analogues tested in competition studies, together with the high affinity of BIM-23027, indicate that the majority of receptors in Neuro2A cells are of the sst2 subtype. 2. The stable radioligand, [125I]-BIM-23027, bound with high affinity (Kd = 13 pM, Bmax = 0.2 pmol mg-1 protein) to Neuro2A cell membranes, but its binding was only partially reversible at room temperature and below. Thus at 4 degrees C, only 36% of the bound ligand dissociated within 2 h. In contrast, 60% of the ligand dissociated at 15 degrees C and 89% of the ligand dissociated at 37 degrees C. 3. Equilibrium binding of [125I]-BIM-23027 was partially (25%) inhibited by 10 microM GTP, and by 120 mM NaCl (42% inhibition) but this inhibition was increased to 75% when sodium chloride and GTP were added together. This effect of GTP and sodium chloride was also seen in dissociation experiments. After incubation to equilibrium with [125I]-BIM-23027, dissociation was initiated with excess unlabelled ligand in the presence of GTP (10 microM) and sodium chloride (120 mM). Under these conditions 67% of the ligand dissociated at 4 degrees C, 81% at 15 degrees C and 93% at 37 degrees C. Binding was totally inhibited by pretreatment of cells with pertussis toxin. 4. Functionally, BIM-23027 inhibited forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner with an IC50 of 1.0 nM and a maximal inhibition of 37%. This effect was abolished by pretreatment of the cells with pertussis toxin. However, unlike in studies reported with the recombinant sst2 receptor, no rise in intracellular calcium concentration was observed with SRIF-14. 5. We conclude that Neuro2A cells provide a stable neuronal cell line for the study of functionally coupled endogenous somatostatin receptors of the sst2 type. In addition, we have found that activation of the receptor is associated with ligand-receptor internalisation.
Prostate cancer (PC) is one of the most frequently diagnosed cancers and a leading cause of cancer-related deaths in Western society. Current PC therapies prevalently target the functions of androgen receptor (AR) and may only be effective within short time periods, beyond which the majority of PC patients progress to castration-resistant PC (CRPC) and metastatic disease. The role of estradiol/estradiol receptor (ER) axis in prostate transformation and PC progression is well established. Further, considerable efforts have been made to investigate the mechanism by which somatostatin (SST) and somatostatin receptors (SSTRs) influence PC growth and progression. A number of therapeutic strategies, such as the combination of SST analogs with other drugs, show, indeed, strong promise. However, the effect of the combined treatment of SST analogs and estradiol on proliferation, epithelial mesenchyme transition (EMT) and migration of normal- and cancer-derived prostate cells has not been investigated so far. We now report that estradiol plays anti-proliferative and pro-apoptotic effect in non-transformed EPN prostate cells, which express both ERα and ERβ. A weak apoptotic effect is observed in transformed CPEC cells that only express low levels of ERβ. Estradiol increases, mainly through ERα activation, the expression of SSTRs in EPN, but not CPEC cells. As such, the hormone enhances the anti-proliferative effect of the SST analog, pasireotide in EPN, but not CPEC cells. Estradiol does not induce EMT and the motility of EPN cells, while it promotes EMT and migration of CPEC cells. Addition of pasireotide does not significantly modify these responses. Altogether, our results suggest that pasireotide may be used, alone or in combination with other drugs, to limit the growth of prostate proliferative diseases, provided that both ER isoforms (α and β) are present. Further investigations are needed to better define the cross talk between estrogens and SSTRs as well as its role in PC.
Certain human carcinomas have demonstrated a distinct expression of somatostatin receptors. Data on somatostatin receptor expression in follicular thyroid cancer and anaplastic thyroid cancer has been limited and conflicting. This study seeks to characterize somatostatin receptor expression in follicular thyroid cancer and anaplastic thyroid cancer and to assess the effects of somatostatin analogues.
1. Receptor-dependent internalization of somatostatin (SRIF) agonists has been a matter of controversy probably because [125I]Tyr11-SRIF-14 is rapidly degraded. We have studied the internalization of a stable somatostatin analogue, [125I]-BIM-23027, in a neuronal cell line, Neuro2A, which natively expresses somatostatin sst2 receptors. 2. Incubation of Neuro2A cells with [125I]-BIM-23027 at 37 degrees C resulted in a time-dependent internalization of the ligand, which reached a maximum at 30 min. Acid-washing showed that cell-surface binding of the ligand accounted for only 34% of total binding at this time. Internalization was dramatically reduced at 15 degrees C. 3. Internalization of [125I]-BIM-23027 was prevented by inclusion of unlabelled somatostatin receptor agonists in a concentration-dependent manner. The IC50 values for inhibition of [125I]-BIM-23027 internalization were approximately 100 fold lower than for inhibition of [125I]-BIM-23027 binding to membrane homogenates but followed the same rank order of potencies. 4. Disruption of G-protein coupling by treatment with pertussis toxin caused a 60% reduction in internalization of ligand. A combination of antimycin (50 nM) and deoxyglucose (50 mM) pretreatment, which leads to a depletion of cellular ATP, decreased internalization of [125I]-BIM-23027 by 66% of control and increased the proportion of surface-bound ligand. Hypertonic sucrose, which prevents clathrin-mediated endocytosis, reversibly abolished the internalization of ligand without increasing the proportion bound at the cell surface. 5. After internalization of [125I]-BIM-23027, approximately half of the ligand was recycled back to the extracellular medium within 20 min at 37 degrees C. This finding suggests that the intracellular content of [125I]-BIM-23027 reaches a steady state which is determined by the rates of both internalization and recycling of the ligand. In contrast to studies in which the internalization of [125I]-Tyr11-SRIF-14 was examined, neither internalized nor recycled [125I]-BIM-23027 was degraded to its component amino acids. 6. These findings indicate that the somatostatin agonist, [125I]-BIM-23027, is internalized in a receptor-dependent manner which involves clathrin-coated pits in Neuro2A cells. Furthermore, much of the internalized ligand is rapidly recycled back to the extracellular medium without undergoing significant degradation.
Somatostatin receptor (SSTR) expression is positively correlated with tumor size and inversely correlated with epidermal growth factor receptor (ErbB) levels and tumor differentiation. In the present study, we compared SSTR1-5 and ErbB1-4 mRNA and protein expression in two breast cancer cell lines: MCF-7 (ER+) and MDA-MB-231 (ERalpha-).
In the retina, somatostatin (SRIF) acts as a neuromodulator by interacting with specific SRIF subtype (sst) receptors. The aim of this study was to detect mRNAs for sst(1-5) receptors by semiquantitative RT-PCR and to determine the cellular localization of either SRIF or individual SRIF receptor immunoreactivities. Size, density and absolute number of immunolabeled somata were measured using computer-assisted image analysis. With RT-PCR we found that all five sst receptor mRNAs were expressed, with highest levels of sst(2) and sst(4) receptors. SRIF immunolabeling was localized to sparse-occurring amacrine cells in the inner nuclear layer (INL) and to displaced amacrine cells in the ganglion cell layer (GCL). sst(2A) receptors were localized to protein kinase- (PKC) immunoreactive (IR) rod bipolar cells, calbindin- (CaBP-) IR horizontal cells, tyrosine hydroxylase- (TH-) IR amacrine cells and glycinergic amacrine cells. None of the sst(2A)-IR amacrine cells were found to express parvalbumin (PV) immunoreactivity. sst(4) receptor immunolabeling was localized to CaBP-IR and CaBP-non-IR cells in the GCL that originated long process bundles in the GC axon layer. These cells were not observed after optic nerve transection and they were therefore interpreted as ganglion cells. Quantitative analysis showed that all of the PKC-IR rod bipolar cells, CaBP-IR horizontal cells, and TH-IR amacrine cells and 5% of the glycinergic amacrine cells expressed sst(2A) receptors. In addition, 4-6% of the putative ganglion cells expressed sst(4) receptors. The localization of SRIF to sparse-occurring retinal neurons, together with the widespread expression of sst(2A) and sst(4) receptors suggests that SRIF acts at multiple levels of retinal circuitry. These results provide a database for investigations of the functional retinal networks in mice with genetic alterations of somatostatinergic transmission.
Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.
1. [125I]-[LTT]SRIF-28 and [125I]-SMS 201-995 were used to identify and characterize somatostatin (SRIF) receptors localized in rat lung tissue. In vitro autoradiography of rat lung tissue sections showed the existence of specific, high affinity binding sites for [125I]-[LTT]SRIF-28 without any significant specific binding of the sst2/sst5-receptor selective ligand [125I]-SMS 201-995. 2. In radioligand binding studies, specific binding of [125I]-[LTT]SRIF-28 to membranes of rat lung was linearly related to the concentration of membrane protein used with only a small portion of nonspecific binding. With [125I]-SMS 201-995 no specific binding could be observed up to a membrane concentration of 0.1 mg of protein/assay tube. 3. [125I]-[LTT]SRIF-28 bound rapidly to rat lung membranes with an apparent association rate constant (kapp) of 1.8 +/- 0.1 h-1 (n = 3). The equilibrium of specific binding was reached after an incubation period of approximately 90 min at room temperature and remained constant for the next 3 h. The association rate constant (k1) was calculated to be 3.7 x 10(10) M-1 h-1. The dissociation reaction followed first order kinetics with a dissociation rate constant (k-1) = 0.44 +/- 0.07 h-1 corresponding to a half-time of 95 +/- 15 min (n = 3). From these kinetic experiments an equilibrium dissociation constant (KD) for the binding of [125I]-[LTT]SRIF-28 was calculated to be 11.9 pM. 4. Saturation binding of [125I]-[LTT]SRIF-28 revealed an equilibrium dissociation constant (KD) of 50.1 pM (pKD = 10.3 +/- 0.1; n = 3) and a receptor density (Bmax) of 78 +/- 3 fmol mg-1 protein. A Hill coefficient not significantly different from 1 indicated saturable binding to a single class of high affinity binding sites. 5. Specific binding of [125I]-[LTT]SRIF-28 to rat lung membranes was inhibited by SRIF-14, SRIF-28 and different SRIF analogues. SRIF and different synthetic short chain SRIF analogues exhibited the following rank order of potency: SRIF-28 > SRIF-14 > CGP 23996 >> RC 160 > BIM 23014 > SMS 201- 995 > BIM 23056 > MK 678. 6. The binding affinities for SRIF and the various SRIF analogues determined using rat lung tissue were in close correlation to those obtained with Chinese hamster ovary (CHO) cells stably expressing sst, (r = 0.92) and sst4 (r = 0.95) receptors, respectively. 7. Reverse transcriptase--polymerase chain reaction (RT-PCR) showed the predominant expression of mRNA specific for sst4 receptors as well as some weak sst1 mRNA expression. 8. The findings suggest that sst4 receptor expression is the predominant form of the somatostatin receptors identified in rat lung tissue. In this study we demonstrated for the first time the existence of sst4 receptors in mammalian tissue.
Somatostatin receptors (SSTRs) are G protein-coupled receptors (GPCRs) known to regulate exocrine secretion, neurotransmission, and inhibit endogenous cell proliferation. SSTR subtypes (SSTR1-SSTR5) exhibit homo- or heterodimerization with unique signaling characteristics. Melanocortin receptor accessory protein 1 (MRAP1) functions as an allosteric modulator of melanocortin receptors and some other GPCRs. In this study, we investigated the differential interaction of MRAP1 and SSTRs and examined the pharmacological modulation of MRAP1 on mouse SSTR2/SSTR3 and SSTR2/SSTR5 heterodimerization in vitro. Our results show that the mouse SSTR2 forms heterodimers with SSTR3 and SSTR5 and that MRAP1 selectively interacts with SSTR3 and SSTR5 but not SSTR2. The interactive binding sites of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 locate on SSTR3 and SSTR5 but not SSTR2. The binding sites of MRAP1 to SSTR3 are extensive, while the ones of SSTR5 are restricted on transmembrane region six and seven. The heterodimerization of mouse SSTR2, SSTR3, and SSTR5 can be modulated by binding protein in addition to an agonist. Upregulation of extracellular signal-regulated kinases phosphorylation, p27Kip1, and increased cell growth inhibition with the co-expression of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 suggest a regulatory effect of MRAP1 on anti-proliferative response of two SSTR heterodimers. Taken together, these results provide a new insight of MRAP1 on the maintenance and regulation of mouse SSTR dimers which might be helpful to better understand the molecular mechanism involving SSTRs in tumor biology or other human disorders.
Inhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80-90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.
Little is known about the role of the neuropeptide somatostatin (SST) in myocardial ischemia/reperfusion injury and cardioprotection. Here, we investigated the direct cardiocytoprotective effect of SST on ischemia/reperfusion injury in cardiomyocyte cultures, as well as the expression of SST and its receptors in pig and human heart tissues. SST induced a bell-shaped, concentration-dependent cardiocytoprotection in both adult rat primary cardiomyocytes and H9C2 cells subjected to simulated ischemia/reperfusion injury. Furthermore, in a translational porcine closed-chest acute myocardial infarction model, ischemic preconditioning increased plasma SST-like immunoreactivity. Interestingly, SST expression was detectable at the protein, but not at the mRNA level in the pig left ventricles. SSTR1 and SSTR2, but not the other SST receptors, were detectable at the mRNA level by PCR and sequencing in the pig left ventricle. Moreover, remote ischemic conditioning upregulated SSTR1 mRNA. Similarly, SST expression was also detectable in healthy human interventricular septum samples at the protein level. Furthermore, SST-like immunoreactivity decreased in interventricular septum samples of patients with ischemic cardiomyopathy. SSTR1, SSTR2, and SSTR5 but not SST and the other SST receptors were detectable at the mRNA level by sequencing in healthy human left ventricles. In addition, in healthy human left ventricle samples, SSTR1 and SSTR2 mRNAs were expressed especially in vascular endothelial and some other cell types as detected by RNA Scope® in situ hybridization. This is the first demonstration that SST exerts a direct cardiocytoprotective effect against simulated ischemia/reperfusion injury. Moreover, SST is expressed in the heart tissue at the peptide level; however, it is likely to be of sensory neural origin since its mRNA is not detectable. SSTR1 and SSTR2 might be involved in the cardioprotective action of SST, but other mechanisms cannot be excluded.
Angiogenesis is characterised by activation, migration and proliferation of endothelial cells and is central to the pathology of cancer, cardiovascular disease and chronic inflammation. Somatostatin is an inhibitory polypeptide that acts through five receptors (sst 1, 2, 3, 4, 5). Sst has previously been reported in endothelium, but their role remains obscure. Here, we report the expression of sst in human umbilical vein endothelial cells (HUVECs) in vitro, during proliferation and quiescence. A protocol for culturing proliferating and quiescent HUVECs was established, and verified by analysing cell cycle distribution in propidium-iodide-stained samples using flow cytometry. Sst mRNA was then quantified in nine proliferating and quiescent HUVEC lines using quantitative reverse transcriptase-polymerase chain reaction. Sst 2 and 5 were preferentially expressed in proliferating HUVECs. All samples were negative for sst 4. Sst 1 and 3 expression and cell cycle progression were unrelated. Immunostaining for sst 2 and 5 showed positivity in proliferating but not quiescent cells, confirming sst 2 and 5 protein expression. Inhibition of proliferating cells with somatostatin analogues Octreotide and SOM230, which have sst 5 activity, was found (Octreotide 10(-10)-10(-6) M: 48.5-70.2% inhibition; SOM230 10(-9)-10(-6) M: 44.9-65.4% inhibition) in a dose-dependent manner, suggesting that sst 5 may have functional activity in proliferation. Dynamic changes in sst 2 and 5 expression during the cell cycle and the inhibition of proliferation with specific analogues suggest that these receptors may have a role in angiogenesis.
Somatostatin, a growth hormone-release inhibiting peptide, exerts antiproliferative and antiangiogenic effects on tumor cells. However, the short half-life of somatostatin limits its application in human therapy, and long-acting somatostatin fusion protein is also limited by its severe terminal degradation. Therefore, oncolytic virus delivery system was introduced to express somatostatin fusion protein and the anti-tumor effects of both somatostatin and oncolytic virus were combined to destroy tumor tissues. Here, a vaccinia VG9/(SST-14)2-HSA recombinant was constructed by replacing somatostatin fusion gene into TK locus of attenuated VG9 strain via homologous recombination. Results showed that vaccinia VG9/(SST-14)2-HSA possessed a combined anti-tumor effect on sstr-positive tumor cells in vitro. In the tumor burden models, BALB/c mice with complete immunity are most suitable for evaluating tumor regression and immune activation. Complete tumor regression was observed in 3 out of 10 mice treated with vaccinia VG9/TK- or VG9/(SST-14)2-HSA, and the survival of all mice in both groups was significantly prolonged. Besides, vaccinia VG9/(SST-14)2-HSA is more effective in prolonging survival than VG9/TK-. Vaccinia VG9/(SST-14)2-HSA exerts a combined anti-tumor efficacy including the oncolytic ability provided by the virus and the anti-tumor effect contributed by (SST-14)2-HSA, which is expected to become a potent therapeutic agent for cancer treatment.
The concept of delivering nanoformulations to desired tissues by means of targeting membrane receptors of high local abundance by ligands anchored to the nanocarrier has gained a lot of attention over the last decade. Currently, there is no unanimous opinion on whether surface functionalization of nanocarriers by targeting ligands translates into any real benefit in terms of pharmacokinetics or treatment outcomes. Having examined the published nanocarriers designed to engage with somatostatin receptors, we realized that in the majority of cases targetability claims were not supported by solid evidence of targeting ligand-targeted receptor coupling, which is the very crux of a targetability concept. Here, we present an approach to characterize targetability of mesoporous silica-based nanocarriers functionalized with ligands of somatostatin receptors. The targetability proof in our case comes from a functional assay based on a genetically-encoded cAMP probe, which allows for real-time capture of receptor activation in living cells, triggered by targeting ligands on nanoparticles. We elaborate on the development and validation of the assay, highlighting the power of proper functional tests in the characterization pipeline of targeted nanoformulations.
The development of somatostatin analogs for the treatment of pituitary Cushing's disease has been based on somatostatin receptor expression analyses of small cohorts of pituitary adenomas. Additionally, the classification of pituitary adenomas has recently changed. To enable progress with this treatment option, we assessed somatostatin receptors in a large cohort of corticotroph and other pituitary adenomas according to the new WHO classification of endocrine tumors. Paraffin-embedded tumor samples of 88 corticotroph pituitary adenomas and 30 nonadenomatous pituitary biopsies were analyzed after processing into tissue microarrays and immunohistochemical staining for SSTR 1, SSTR2A, SSTR3, SSTR4, and SSTR5. For comparison, 159 other noncorticotroph pituitary adenomas were analyzed. SSTR3 expression was higher in corticotroph adenomas compared to PIT-1-positive, gonadotroph, and nonfunctioning pituitary adenomas (p < 0.0001, p = 0.0280, and p < 0.0001, respectively). This was also the case for the expression of SSTR5 (p = 0.0003, p < 0.0001, and p < 0.0001, respectively). SSTR2A expression was higher compared to gonadotroph and nonfunctioning pituitary adenomas (p = 0.0217 and 0.0126, respectively) while PIT-1-positive adenomas showed even higher SSTR2A expression (p < 0.0001). SSTR2A and SSTR5 were both expressed higher in nonadenomatous pituitary biopsies than in pituitary adenomas (p = 0.0126 and p = 0.0008, respectively). There are marked expression differences of SSTR1-5 as well as changes in expression in recurrent disease that need to be addressed when looking for other possible substances for the treatment of Cushing's disease. SSTR2A, SSTR3, and SSTR5 seem to be most suitable biomarkers for a targeted therapy with somatostatin analogs.
Somatostatin (SRIF), by acting mainly through sst2 and sst5 receptors, is a potent inhibitor of hormonal secretion by the human anterior pituitary gland. However, the pattern of protein expression of these SRIF receptors remains unknown during pituitary development. To get further insights into the physiological role of SRIF receptors in human development and pituitary function, the present study examined the developmental expression of the sst2 and sst5 receptors in the individual cell types of the anterior human pituitary. Thirteen fetal human pituitaries were investigated between 13 to 38 weeks of gestation (WG) by double-labeling immunofluorescence with antibodies raised against sst2 or sst5 receptors and GH, LH, FSH, TSH, or pro-opiomelanocortin proteins. SRIF immunoreactivity in the hypothalamus and median eminence was investigated at the same developmental ages. Immunoreactivity for the sst2 receptor was evident as early as 13 to 15 WG and onward mainly in TSH-, LH-, and FSH-expressing cells, whereas sst5 immunoreactivity was apparent at the late development stages (35-38 WG). GH-expressing cells mainly expressed sst5 immunoreactivity. SRIF-positive fibers and cells were detected as soon as 13 to 16 WG in the hypothalamus and median eminence and their densities increased with gestational age. The early appearance of hypothalamic SRIF cells and fibers suggests a physiological link between SRIF and its receptors during pituitary development. Whereas sst2 receptors might play a primary role in the differentiation and regulation of TSH, LH, and FSH cells, sst5 receptors appear to be mainly involved in GH regulation from birth onward.
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