Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumours

Somatostatin has been identified as having anti-proliferative, anti-angiogenic and pro-apoptotic actions in many tumour systems, and these effects are mediated through a family of five transmembrane G-protein coupled SRIF receptors. Ovarian cancer is the commonest gynaecological malignancy in the UK and maintenance therapy is urgently required. Native somatostatin expression and its receptors sst1,2,3 and 5 were studied with immunohistochemistry in 63 malignant and 35 benign ovarian tumours of various histological types. Fifty-seven out of 63 (90%) of malignant and 26/35 (74%) benign tumours expressed somatostatin. Receptors sst1,2,3 and 5 were expressed variably in epithelial, vascular and stromal compartments for both benign and malignant tumours. Somatostatin was found to correlate significantly with stromal sst1 (P=0.008), epithelial sst1 (P<0.001), stromal sst2 (P=0.019), vascular sst2 (P=0.026), epithelial sst3 (P=0.026), stromal sst5 (P=0.013) and vascular sst5 (P=0.038). Increased expression of native somatostatin correlating with somatostatin receptors in malignant ovarian tumours raises the possibility that either synthetic somatostatin antagonists or receptor agonists may have therapeutic potential

Expression of the SST receptor 2 in uveal melanoma is not a prognostic marker

Introduction: Uveal melanoma (UM) cells and neurohormone-producing cells both originate from the neural crest. Somatostatin receptors subtype 2 (SSTR2) are over-expressed in several tumors, often from neuroendocrine origin, and synthetic antagonists like octreotide and octreotate are being used as diagnostic or therapeutic agents. We investigated the SSTR2 expression in UM, and determined whether this expression was related to prognosis of the disease. Materials and methods: UM cell lines and fresh primary UM samples were tested for SSTR2 expression by autoradiography (AR) using 125I-Tyr3-octreotate. Furthermore, UM cell lines were analyzed for SSTR2 mRNA expression with quantitative real-time RT-PCR. Results: Using AR, cell-surface SSTR2 expression was demonstrated in two UM metastatic cell lines, but no expression was detected in three cell lines derived from primary UM. However, all primary and metastatic UM cell lines showed mRNA expression levels for SSTR2 using quantitative real-time RT-PCR. Only three of 14 primary UM demonstrated moderate SSTR2 expression, and this expression was not significantly associated with tumor-free survival or any tested prognostic factor. Conclusions: Based on the rare and low expression of SSTR2 found in primary UM specimens and in UM cell lines, we conclude that SSTR2 is not widely expressed in UM. Furthermore, SSTR2 expression was not associated with tumor-free survival and prognostic factors. Therefore SSTR2 is not suited as prognostic marker or therapeutic target in UM

Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex

Presynaptic NMDA receptors facilitate the release of glutamate at excitatory cortical synapses and are involved in regulation of synaptic dynamics and plasticity. At synapses in the entorhinal cortex these receptors are tonically activated and provide a positive feedback modulation of the level of background excitation. NMDA receptor activation requires obligatory occupation of a co-agonist binding site, and in the present investigation we have examined whether this site on the presynaptic receptor is activated by endogenous glycine or d-serine. We used whole-cell patch clamp recordings of spontaneous AMPA receptor-mediated synaptic currents from rat entorhinal cortex neurones in vitro as a monitor of presynaptic glutamate release. Addition of exogenous glycine or d-serine had minimal effects on spontaneous release, suggesting that the co-agonist site was endogenously activated and likely to be saturated in our slices. This was supported by the observation that a co-agonist site antagonist reduced the frequency of spontaneous currents. Depletion of endogenous glycine by enzymatic breakdown with a bacterial glycine oxidase had little effect on glutamate release, whereas d-serine depletion with a yeast d-amino acid oxidase significantly reduced glutamate release, suggesting that d-serine is the endogenous agonist. Finally, the effects of d-serine depletion were mimicked by compromising astroglial cell function, and this was rescued by exogenous d-serine, indicating that astroglial cells are the provider of the d-serine that tonically activates the presynaptic NMDA receptor. We discuss the significance of these observations for the aetiology of epilepsy and possible targeting of the presynaptic NMDA receptor in anticonvulsant therapy. © 2014 Elsevier Ltd. All rights reserved

The immunohistochemical localisation of somatostatin receptors 1, 2, 3, and 5 in acoustic neuromas

Aims: Acoustic neuroma is a benign tumour, which develops through an overproliferation of Schwann cells along the vestibular nerve. Somatostatin is a naturally occurring peptide, which exerts antiproliferative and antiangiogenic effects via five membrane bound receptor subtypes. The aim of this study was to determine whether somatostatin receptor subtypes (SSTRs) 1, 2, 3, and 5 are present in acoustic neuromas. Methods: The expression of SSTRs 1, 2, 3, and 5 was studied in both the Schwann cells and blood vessels of eight acoustic neuroma specimens, by means of immunohistochemistry using novel rabbit polyclonal antibodies raised against human SSTR 1, 2, and 5 subtype specific peptides, and a commercial anti-SSTR3 antibody. Results: SSTR2 was the most prevalent subtype in Schwann cells (seven of eight), with intermediate expression of SSTR3 (six of eight), and lower expression of SSTRs 1 and 5 (four of eight and five of eight, respectively). There was ubiquitous vascular expression of SSTR2, with no evidence of SSTR 1, 3, or 5 expression in blood vessels. Conclusion: SSTRs 1, 2, 3, and 5 are differentially expressed in acoustic neuromas. Somatostatin analogues may have a therapeutic role in the management of this rare and challenging condition