The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Jean Claude Reubi - One of the best experts on this subject based on the ideXlab platform.
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Somatostatin and other peptide Receptors as tools for tumor diagnosis and treatment
Neuroendocrinology, 2004Co-Authors: Jean Claude ReubiAbstract:Somatostatin Receptors are expressed in selected human cancers. They are particularly frequently expressed in gastroenteropancreatic neuroendocrine tumors (GEP NET), including both primaries and metastases. The density is often high, the distribution is usually homogeneous. While various Somatostatin receptor subtypes can be expressed in these tumors, sst2 is clearly predominant. These Receptors represent the molecular basis for a number of clinical applications, including symptomatic therapy with cold octreotide in hormone-secreting GEP NET, in vivo diagnostic with Octreoscan to evaluate the extend of the disease, and 90Y-DOTATOC radiotherapy. GEP NET can, however, express peptide Receptors other than Somatostatin Receptors: insulinomas have more glucagon-like peptide 1 Receptors than Somatostatin Receptors, gut NET (carcinoids) may also express cholecystokinin 2, bombesin or vasoactive intestinal peptide Receptors. Often, several of these peptide Receptors are expressed simultaneously in GEP NET, providing a molecular basis for in vivo multireceptor targeting of those tumors.
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A new peptidic Somatostatin agonist with high affinity to all five Somatostatin Receptors.
European Journal of Pharmacology, 2002Co-Authors: Jean Claude Reubi, Beatrice Waser, Klaus-peter Eisenwiener, Hans Rink, Helmut R. MäckeAbstract:Abstract All commercially available Somatostatin analogs for clinical use have a preference for some but not all Somatostatin receptor subtypes. We describe here the synthesis and evaluation in binding and cAMP assays with cell lines stably transfected with sst1–sst5 of a new type of nonapeptide Somatostatin analog with a reduced-sized and stabilized structure, Tyr0–(cyclo- d -Dab–Arg–Phe–Phe– d -Trp–Lys–Thr–Phe) (KE108). All five Somatostatin Receptors subtypes have an extremely high affinity for KE108, equivalent to SS-28 at sst1 and two to four times higher than SS-28 at sst2, sst3, sst4 and sst5. Moreover, the compound has agonistic properties at all five subtypes, since it is able to inhibit the forskolin-stimulated cAMP production in sst1–sst5 cells. It is stable for several hours in human serum. This analog may therefore represent a considerable improvement over commercially available Somatostatin analogs as it will target all Somatostatin receptor subtypes, a particular advantage for cancer-related applications, as human cancers can express concomitantly several Somatostatin receptor subtypes.
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Somatostatin Receptors in nasopharyngeal carcinoma
Virchows Archiv : an international journal of pathology, 2002Co-Authors: Kwok Seng Loh, Beatrice Waser, Luke Tan, Run Sheng Ruan, Edouard Stauffer, Jean Claude ReubiAbstract:Somatostatin Receptors (SS-Rs) are expressed in neuroendocrine tumour tissues where they can be targetted for diagnosis and therapy. This study investigated the presence of SS-Rs in nasopharyngeal carcinoma (NPC), a common cancer in South-East Asia. Nasopharynx biopsy specimens were obtained from 12 NPC patients and 5 patients without tumours. Somatostatin receptor autoradiography was performed using 125I-labelled [Tyr3]-octreotide and 125I-labelled [Leu8, DTrp22, Tyr25]-Somatostatin-28 as radioligands. Of the 12 NPC samples 9 showed moderate to high expression of SS-Rs. These were of the sst2 type, based on the rank order of potency of subtype-selective analogues. The 5 non-neoplastic samples, consisting primarily of granulomatous tissue, did not express measurable amounts of SS-Rs. This study demonstrates for the first time the presence of type 2 SS-R in NPC. These Receptors may play a role in the management of NPC, as is the case for other Somatostatin-expressing tumours.
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Regulatory peptide Receptors in human hepatocellular carcinomas
Gut, 1999Co-Authors: Jean Claude Reubi, B Waser, Arthur Zimmermann, S Jonas, Peter Neuhaus, Ursula Läderach, Bertram WiedenmannAbstract:BACKGROUND—Overexpression of regulatory peptide Receptors in selected human tumours is of diagnostic and therapeutic relevance. AIMS—To evaluate the expression of Somatostatin, vasoactive intestinal peptide (VIP), substance P, cholecystokinin (CCK) A and B, and neurotensin Receptors in hepatocellular carcinoma (HCC). METHODS—In vitro receptor autoradiography for the various peptide Receptors using selective iodinated radioligands on tissue sections in 59 cases of HCC. RESULTS—41% of HCC expressed Somatostatin Receptors; 47% expressed VIP Receptors. VIP Receptors were always identified in non-neoplastic liver tissue. Substance P Receptors were only identified in 5% of HCC but in the majority of their peritumorous and intratumorous vessels. CCK-A and -B and neurotensin Receptors were not detected in HCC. The Somatostatin Receptors showed high affinity for Somatostatin and octreotide. The VIP Receptors had high affinity for VIP, pituitary adenylate cyclase activating peptide (PACAP) 27, and a VIP1 selective analogue, suggesting the presence of VIP1/PACAP II type Receptors. PACAP I Receptors were identified in two cases. Substance P Receptors were all of the NK1 subtype. The density of Somatostatin Receptors in HCC was low compared with the density found in liver metastases of neuroendocrine tumours. The VIP receptor density was always lower in HCC than in adjacent liver tissue. CONCLUSIONS—Somatostatin, VIP, and substance P may have a receptor mediated role in HCC. Substance P Receptors may be involved in regulation of tumour associated blood flow; Somatostatin Receptors and VIP Receptors may mediate tumour growth. Diagnostic and therapeutic evaluation of Somatostatin and VIP analogues may be of interest in receptor positive HCC. Keywords: Somatostatin Receptors; vasoactive intestinal peptide Receptors; substance P Receptors; receptor autoradiography; tumour vasculature
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Expression of Somatostatin Receptors in peritumoral veins of human tumors
Cancer, 1999Co-Authors: Barbara Denzler, Jean Claude ReubiAbstract:BACKGROUND The vascular system of the tumor bed plays an important function in tumor growth regulation. Recent studies have suggested that the vasoactive peptides Somatostatin and substance P may have a potential role in the tumor bed of selected tumors. METHODS In the current study, Somatostatin Receptors were evaluated with in vitro receptor autoradiography using 125I-[Tyr3]-octreotide in the peritumoral vessels of a large group of 215 primary human tumors and 25 metastases of various tumor origin, with particular emphasis on receptor incidence, distribution, homogeneity, and density. RESULTS High affinity Somatostatin Receptors were found in the peritumoral veins of 22 of 22 gastric carcinomas, 25 of 39 breast carcinomas, 15 of 20 renal cell carcinomas, 14 of 27 prostate carcinomas, 4 of 10 endometrial carcinomas, 4 of 11 pancreatic adenocarcinomas, 4 of 13 nonsmall cell lung carcinomas, as well as in 3 of 4 parathyroid adenomas, 3 of 3 medullary thyroid carcinomas, 3 of 23 gastroenteropancreatic tumors, 14 of 25 soft tissue tumors, 3 of 5 melanomas but in none (0 of 13) of the ovarian carcinomas studied. In addition, Somatostatin Receptors were identified in veins surrounding lymph node, bone, and lung metastases of various tumor types. In all investigated tissues, Receptors could not be identified in arteries. There was a considerable variability in the relative number of veins expressing Somatostatin Receptors and in the receptor density levels. Evidence of an overexpression of Somatostatin Receptors could be established in the peritumoral veins of gastric carcinoma when compared with the receptor expression in normal gastric vessels. CONCLUSIONS The expression of Somatostatin Receptors in peritumoral veins appears to be a general, tumor-related, but highly variable phenomenon. Although their pathophysiologic role is unclear, these Receptors may be considered as novel targets for cancer diagnosis and therapy with Somatostatin analogs. Cancer 1999;85:188–98. © 1999 American Cancer Society.
Ujendra Kumar - One of the best experts on this subject based on the ideXlab platform.
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Comparative distribution of Somatostatin and Somatostatin Receptors in PTU-induced hypothyroidism
Endocrine, 2020Co-Authors: Sneha Singh, Rishi K. Somvanshi, Vandana Panda, Ujendra KumarAbstract:Purpose Propylthiouracil (PTU)-induced hypothyroidism is a well-established model for assessing hormonal and morphological changes in thyroid as well as other central and peripheral tissues. Somatostatin (SST) is known to regulate hormonal secretion and synthesis in endocrine tissues; however, nothing is currently known about the distribution of SST and its receptor in hypothyroidism. Method In the present study, the comparative immunohistochemical distribution of SST and Somatostatin Receptors (SSTRs) were analyzed in PTU-induced hypothyroid rats. Rats were treated with PTU for 15 days followed by a co-administration of levothyroxine (LVT) for 15 days. After PTU and LVT treatments (day 30), rats were further administered LVT alone for 15 more days (day 45). The subcellular distribution of SST and SSTR subtypes was determined by peroxidase immunohistochemistry in the thyroid gland collected from control and treated rats. Results SST and SSTR subtypes were found to be moderately expressed in control thyroid tissues. SST and SSTR subtypes like immunoreactivity increased significantly in follicular and parafollicular epithelial cells in the thyroid of PTU-treated rats. The PTU-induced changes in the expression of SST and SSTR subtypes were suppressed by the administration of the LVT. In addition to thyroid tissues, SST and SSTRs expression was also changed in non-follicular tissues including blood vessels, smooth muscle cells, and connective tissue following treatments. Conclusion The present study revealed a distinct subcellular distribution of SST and SSTR subtypes in the thyroid and provides a new insight for the role of SST and SSTR subtypes in hypothyroidism in addition to its well-established role in negative regulation of hormonal secretion.
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characterization of Somatostatin Receptors and associated signaling pathways in pancreas of r6 2 transgenic mice
Biochimica et Biophysica Acta, 2018Co-Authors: Rishi K. Somvanshi, Amrit Jhajj, Michael Heer, Ujendra KumarAbstract:Abstract The present study describes the status of Somatostatin Receptors (SSTRs) and their colocalization with insulin (β), glucagon (α) and Somatostatin (δ) producing cells in the pancreatic islets of 11 weeks old R6/2 Huntington's Disease transgenic (HD tg ) and age-matched wild type ( wt ) mice. We also determined expression of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD) and presynaptic marker synaptophysin (SYP) in addition to signal transduction pathways associated with diabetes. In R6/2 mice, islets are relatively smaller in size, exhibit enhanced expression and nuclear inclusion of m Htt along with the loss of insulin, glucagon and Somatostatin expression. In comparison to wt , R6/2 mice display enhanced mRNA for all SSTRs except SSTR2. In the pancreatic lysate, SSTR1, 4 and 5 immunoreactivity decreases whereas SSTR3 immunoreactivity increases with no discernible changes in SSTR2 immunoreactivity. Furthermore, at the cellular level, R6/2 mice exhibit a receptor specific distributional pattern of SSTRs like immunoreactivity and colocalization with β, α and δ cells. While GAD expression is increased, TH and SYP immunoreactivity was decreased in R6/2 mice, anticipating a cross-talk between the CNS and pancreas in diabetes pathophysiology. We also dissected out the changes in signaling pathway and found decreased activation and expression of PKA, AKT, ERK1/2 and STAT3 in R6/2 mice pancreas. These findings suggest that the impaired organization of SSTRs within islets may lead to perturbed hormonal regulation and signaling. These interconnected complex events might shed new light on the pathogenesis of diabetes in neurodegenerative diseases and the role of SSTRs in potential therapeutic intervention.
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Somatostatin Receptors 1 and 5 heterodimerize with epidermal growth factor receptor agonist dependent modulation of the downstream mapk signalling pathway in breast cancer cells
Cellular Signalling, 2009Co-Authors: Heather L Watt, Geetanjali Kharmate, Ujendra KumarAbstract:Abstract The role of Somatostatin (SST) and epidermal growth factor (EGF) in breast cancer is undisputed; however, the molecular mechanisms underlying their antiproliferative or proliferative effects are not well understood. We initially confirmed that breast tumour tissues express all five Somatostatin Receptors (SSTR1-5) and four epidermal growth factor Receptors (ErbB1-4). Subsequently, to gain insight into the function of SSTRs and ErbBs in oestrogen receptor (ER)-positive (MCF-7) or ERα-negative (MDA-MB-231) breast cancer cells, we defined SSTR1, SSTR5 and ErbB1 mRNA and protein expression in these two tumour cell lines. Consistent with previous studies showing SSTR1/SSTR5 heterodimerization and having seen cell-specific and ligand-selective alterations in receptor expression, we next elucidated whether SSTR1 and SSTR5 functionally interact with ErbB1 using pbFRET analysis. We subsequently determined the effects of SST and EGF either alone, or in combination, on selected downstream signalling molecules such as erk1/2, p38 and JNK. Here, we showed that both SST and EGF influenced erk1/2 phosphorylation and that SST modulated the effects of EGF in a cell-specific manner. We also demonstrated agonist-, time and cell-dependent regulation of p38 phosphorylation. We further investigated modulation of Grb2, SOS, Shc, SH-PTP1 and SH-PTP2. ErbB1 adaptor proteins known to play a role in MAPK activation, Shc, Grb2 and SOS, changed in an agonist- and cell-specific manner whereas, SH-PTP1 and SH-PTP2, adaptor proteins reported to interact with SSTRs, translocated from the cytosol to membrane in a cell-specific manner following SST and/or EGF treatment. Although several previous studies have shown crosstalk between RTKs and GPCRs, there are no reports describing SSTR (GPCR) modulation of ErbBs (RTK) in breast cancer. To the best of our knowledge, this is the first report describing crosstalk/interactions between SSTRs and ErbBs.
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Somatostatin and Somatostatin Receptors
Results and problems in cell differentiation, 2009Co-Authors: Ujendra Kumar, Michael P GrantAbstract:The biological effects of Somatostatin (SST) were first encountered unexpectedly in the late 1960s in two unrelated studies, one by Krulich et al. (1968) who reported on a growth hormone (GH)-releasing inhibitory substance from hypothalamic extracts, and the other, by Hellman and Lernmark (1969), on the presence of a potent insulin inhibitory factor from the extracts of pigeon pancreatic islets. However, the inhibitory substance was not officially identified until 1973 by Guillemin’s group (Brazeau et al. 1973). In both synthetic and naturally occurring forms, this tetradecapeptide, originally coined as somatotropin release-inhibitory factor (SRIF, SST-14) was shown by Brazeau et al. to be the substance controlling hypothalamic GH release. This single achievement not only pioneered SST research but was also duly recognized, as Guillemin shared the 1977 Nobel Prize in Medicine. The following years bequeathed an exponential increase in SST-related studies. It soon became clear that SST-synthesis was not restricted to the hypothalamus. Its production is widely distributed throughout the central nervous system (CNS), peripheral neurons, the gastrointestinal tract, and the pancreatic islets of Langerhans (Luft et al. 1974; Arimura et al. 1975; Dubois 1975; Hokfelt et al. 1975; Orci et al. 1975; Pelletier et al. 1975; Polak et al. 1975; Patel and Reichlin 1978). In fact, SST-like immunoreactivity can be found throughout various tissues of vertebrates and invertebrates, including the plant kingdom (Patel 1992; Tostivint et al. 2004). Given its broad anatomical distribution, it is no wonder that SST produces a wide spectrum of biological effects. Generally regarded as an inhibitory factor, SST can function either locally on neighboring cells or distantly through the circulation, to regulate such physiological processes as glandular secretion, neurotransmission, smooth muscle contractility, nutrient absorption, and cell division (Reichlin 1983a, b; Patel 1992, 1999; Patel et al. 2001; Barnett 2003).
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Somatostatin Receptors in primary human breast cancer quantitative analysis of mrna for subtypes 1 5 and correlation with receptor protein expression and tumor pathology
Breast Cancer Research and Treatment, 2005Co-Authors: Ujendra Kumar, S I Grigorakis, Heather L Watt, Ramakrishnan Sasi, L Snell, Peter H Watson, S ChaudhariAbstract:Somatostatin Receptors (SSTRs) have been identified in most hormone-producing tumors as well as in breast cancer. In the present study, we determined SSTR1–5 expression in primary ductal NOS breast tumors through semi-quantitative RT-PCR and immunocytochemistry. The results from the analysis of 98 samples were correlated with several key histological markers and receptor expression. All five SSTR subtypes are variably expressed at the mRNA level in breast tumors with 91% of samples showing SSTR1, 98% SSTR2, 96% SSTR3, 76% SSTR4, and 54% SSTR5. SSTR1–5 are localized to both tumor cells and the surrounding peritumoral regions as detected by immunocytochemistry. Levels of SSTR mRNA, when corrected for β-actin levels, were highest for SSTR3 followed by SSTR1, SSTR2, SSTR5, and SSTR4. Furthermore, there was good correlation between mRNA and protein expression with 84% for SSTR1, 79% for SSTR2, 89% for SSTR3, 68% for SSTR4, 68% for SSTR5, and 78% for all five Receptors. SSTR1, 2 and 4 were correlated with ER levels whereas SSTR2 showed an additional correlation with PR levels. These correlations were independent of patient age and histological grade. Moreover, using immunocytochemistry, blood vessels exhibited receptor-specific localization for SSTR2 and SSTR5. Our results indicate significant correlations between mRNA and protein expression along with receptor-specific correlations with histological markers as well as ER and PR levels. Differential distribution of SSTR subtypes in tumors and receptor-specific expression in vascular structures may be considered as a novel diagnosis for breast tumors with receptor subtype agonists.
Volker Höllt - One of the best experts on this subject based on the ideXlab platform.
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localization of five Somatostatin Receptors in the rat central nervous system using subtype specific antibodies
Journal of Physiology-paris, 2000Co-Authors: Stefan Schulz, Manuela Händel, Matthias Schreff, Harald Schmidt, Volker HölltAbstract:Abstract The cloning of five members of the Somatostatin receptor family, sst 1 -sst 5 , as well as two isoforms of the Somatostatin receptor 2, sst 2A and sst 2B , enabled us to generate specific anti-peptide antisera against unique sequences in the carboxyl-terminal tail of each Somatostatin receptor subtype. We used these antibodies in multicolor immunofluorescent studies aimed to examine the regional and subcellular distribution of Somatostatin Receptors in adult rat brain. Several findings are notable: The cloned sst 1 receptor is primarily localized to axons, and therefore most likely functions in a presynaptic manner. The cloned sst 2 receptor isoforms exhibit strikingly different distributions, however, both sst 2A and sst 2B are confined to the plasma membrane of neuronal somata and dendrites, and therefore most likely function in a postsynaptic manner. The cloned sst 3 receptor appears to be excluded from ‘classical’ pre- or postsynaptic sites but is selectively targeted to neuronal cilia. The cloned sst 4 receptor is preferentially distributed to distal dendrites, and therefore most likely functions postsynaptically. The cloned sst 5 receptor was not detectable in the adult rat brain, however, prominent sst 5 expression was found in the pituitary. Furthermore, sst 1 -containing axons either co-contained Somatostatin or were closely apposed by Somatostatin-positive terminals in a regional-specific manner. Neuronal somata and dendrites containing either sst 2A , sst 2B or sst 4 were found to exist in close proximity, although not necessarily synaptically linked, to Somatostatin-positive terminals. Together, in the central nervous system the effects of Somatostatin are mediated by several different receptor proteins which are distributed with considerable regional overlap. However, there appears to be a high degree of specialization among Somatostatin receptor subtypes with regard to their subcellular targeting. This subtype-selective targeting may be the underlying principal of organization that allows Somatostatinergic modulation of neuronal activity via both pre- and postsynaptic mechanisms.
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Immunohistochemical determination of five Somatostatin Receptors in meningioma reveals frequent overexpression of Somatostatin receptor subtype sst2A.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000Co-Authors: Solveig Schulz, Raimund Firsching, Knut Dietzmann, S U Pauli, Manuela Händel, Volker HölltAbstract:Meningioma is one of a variety of human tumors that exhibit a very high density of Somatostatin Receptors and in many cases show a true positive Somatostatin receptor scintigraphy. However, the level of expression of individual Somatostatin receptor proteins in meningioma has not been investigated. We have recently developed a panel of Somatostatin receptor subtype-specific antibodies that effectively stain formalin-fixed, paraffin-embedded tumor tissue (S. Schulz et al., Clin. Cancer Res., 4: 2047-2052, 1998). In the present study, we have used these antibodies to determine the Somatostatin receptor status of 40 randomly selected meningiomas. Immunoreactive staining for all Somatostatin Receptors was clearly located at the plasma membrane of the tumor cells and completely blocked with antigenic peptide. The vast majority of tumors (29 cases; 70%) were positive for sst2A immunoreactivity; among these, 20 (69%) tumors showed high levels of sst2A immunoreactivity. In contrast, all other Somatostatin Receptors were only detected sporadically, and none of these cases revealed a particularly strong staining. However, it is uncertain to what extent Somatostatin receptor-immunoreactive staining intensity may translate into Somatostatin receptor protein expression on the tumor cells. Therefore, in a prospective study, 16 surgically removed meningiomas were collected, and the level of sst2A expression was determined using Western blot analysis. Whereas sst2A was readily detectable as a broad band migrating at Mr 70,000 in 12 (75%) of these tumors, 8 tumors (50%) showed particularly high levels of immunoreactive sst2A Receptors. There was an excellent correlation (P < 0.001) between the level of sst2A protein expression detected in Western blots and the sst2A- immunoreactive staining seen in tissue sections. Thus, the frequent overexpression of the sst2A receptor may explain the high tracer uptake often observed in meningioma patients during Somatostatin receptor scintigraphy. Moreover, this simple immunohistochemical method could prove useful in identifying those cases of recurrent disease that may possibly respond to therapy with sst2-selective agonists.
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immunocytochemical detection of Somatostatin Receptors sst1 sst2a sst2b and sst3 in paraffin embedded breast cancer tissue using subtype specific antibodies
Clinical Cancer Research, 1998Co-Authors: Solveig Schulz, Wolfgang Weise, Albert Roessner, Harald Schmidt, J Schmitt, D Wiborny, Suzanne M Olbricht, C Gramsch, Volker HölltAbstract:The long-acting Somatostatin analogue octreotide (SMS 201-995) inhibits growth of certain breast cancer cell lines in vivo and in vitro. Because the antiproliferative action of octreotide depends on at least the presence of Somatostatin Receptors, it is crucial to determine the pattern of Somatostatin receptor protein expression on the tumor cells. In the present study, we have raised polyclonal antibodies to Somatostatin receptor subtypes (ssts) sst1, sst2A, sst2B, and sst3 using peptides corresponding to their COOH-terminal sequences. These antisera were used for immunocytochemical staining of paraffin sections of 33 primary breast cancers. Somatostatin receptor-like immunoreactivity (Li) was predominantly localized to the plasma membrane of the tumor cells. In the vast majority of positively stained tumors, Somatostatin receptor-Li was uniformly present on nearly all tumor cells. Both the level and the pattern of expression of ssts varied greatly between individual carcinomas. sst2A-Li and/or sst2B-Li was detectable in 28 tumors (85%); among these, 14 tumors (42%) showed particularly high levels of sst2-Li. sst1-Li was found in 17 (52%) cases and sst3-Li in 16 (48%) cases. The expression of ssts was independent of patient age, menopausal status, diagnosis, histological grade, and levels of estrogen and progesterone Receptors. The immunocytochemical determination of Somatostatin receptor status allows direct detection of receptor protein on the tumor cells and, hence, may provide more precise information than reverse transcription-PCR for predicting response to octreotide therapy in breast cancer.
Jean A. Laissue - One of the best experts on this subject based on the ideXlab platform.
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immunohistochemical localization of Somatostatin Receptors sst2a in human tumors
American Journal of Pathology, 1998Co-Authors: Jean Claude Reubi, Jean A. Laissue, Beatrice Waser, Andreas Kappeler, William R Hipkin, Agnes SchonbrunnAbstract:Human tumors frequently express Somatostatin Receptors. However, none of the receptor subtype proteins have been individually visualized in normal or neoplastic human tissues. Here, the distribution of the sst2A receptor was investigated using immunohistochemistry with the specific anti-peptide antibody R2–88 in 47 human tumors. All tumors selected for their abundance of sst2 mRNA and/or strong binding of the sst2-preferring ligand 125 I-labeled Tyr 3 -octreotide were specifically immunostained with R2–88. Conversely, all tumors without Somatostatin binding or expressing predominantly other Somatostatin receptor subtype mRNAs (sst1 or sst3) were not specifically immunostained by R2–88. Specificity was shown in immunoblots, demonstrating receptor migration as a 70-kd broad band. In immunohistochemical and immunoblotting experiments, the abolition of staining after antibody blockade with antigen peptide was demonstrated. Immunostaining was identified in cryostat and in formalin-fixed, paraffin-embedded sections. Heat-induced epitope retrieval was necessary to visualize sst2A Receptors in formalin-fixed sections. Moreover, because of occasional high nonspecific staining, the demonstration of complete abolition of immunostaining by treatment with antigen peptide was a prerequisite for the correct identification of sst2A-positive tumors. The sst2A Receptors were clearly located at the membrane of the tumor cells. These results provide the first localization of a Somatostatin receptor subtype in human tissues at the cellular level. The sst2A receptor identification and visualization in tumors with simple immunohistochemical methods in formalin-fixed, paraffin-embedded material will open new diagnostic opportunities for pathologists.
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Somatostatin Receptors and their subtypes in human tumors and in peritumoral vessels
Metabolism: clinical and experimental, 1996Co-Authors: Jean Claude Reubi, Jean A. Laissue, Jean-claude Schaer, Beatrice WaserAbstract:Somatostatin Receptors are expressed by a large variety of human tumors. In vitro receptor autoradiographic studies have shown that these tumors can express more than one Somatostatin receptor subtype. Whereas the majority of tumors bind octreotide with high affinity, some, ie, prostate tumors, bind octreotide with low affinity only. The discovery of five Somatostatin receptor subtypes, ss%.s, by gene cloning has increased our understanding of Somatostatin receptor structure and function. Using in situ hybridization techniques, we found that various human tumors, identified as Somatostatin receptor-positive binding studies, expressed sst2 mRNA in the majority of cases, whereas sstl and sst3 were less frequent. Often, all three sst were expressed simultaneously. In another recent in situ hybridization study, primary prostate cancers were shown to preferentially express sstl rather than sst2 or sst3. Moreover, a high incidence of ssts was found in growth hormone (GH)-producing pituitary adenomas and, to a lesser extent, in active pituitary adenomas; gastroenteropancreatic (GEP) tumors showed all possible combinations, but with a predominance of sst2. Overall, the presence of sst2 mRNA and/or ssts generally correlated with the presence of octreotide-binding sites, but with exceptions. These results indicate the highlY variable abundance of sst mRNAs in individual Somatostatin receptor-containing tumors. Somatostatin Receptors were not only found in tumoural tissue, but also in the peritumoral vascular system. This was particularly well studied in colorectal carcinomas, where the peritumoral veins were shown to express in all cases a high density of Somatostatin Receptors, probably of the sst2 type, binding octreotide with high affinity. Therefore, the host peritumoral vascular system may be a possible target of Somatostatin action in tumor development. Somatostatin may act locally on tumor growth through two different mechanisms dependent on local Somatostatin receptor expression: through direct action on tumor cells or through action on peritumoral vessels, which may alter the hemodynamics of the tumoral blood circulation. Copyright © 1996 by W.B. Saunders Company
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Expression of Somatostatin Receptors in normal, inflamed, and neoplastic human gastrointestinal tissues.
Annals of the New York Academy of Sciences, 1994Co-Authors: Jean Claude Reubi, Jean A. Laissue, Beatrice Waser, Ursula Horisberger, Jean-claude SchaerAbstract:The multiple actions of Somatostatin are mediated by specific membrane-bound Receptors present in all Somatostatin target tissues, such as brain, pituitary, pancreas, gastrointestinal tract, and kidney. For instance, in the human gastrointestinal tract, three different types of tissue compartments express Somatostatin Receptors: the gastrointestinal mucosa, the peripheral nervous system, and the gut-associated lymphoid tissue, where the Receptors are preferentially located in germinal centers. In all these cases, Somatostatin binding is of high affinity and specific for bioactive Somatostatin analogues. Somatostatin Receptors are also expressed in pathological states, such as cancers. A particular abundance is found in neuroendocrine tumors of the gastrointestinal tract. Ninety percent of the carcinoids and a majority of islet cell carcinomas, including their metastases, usually have a high density of Somatostatin Receptors. Several different Somatostatin-receptor subtypes can be expressed by these tumors, the SSTR2 subtype being the most frequently and abundantly expressed. The Somatostatin Receptors in tumors are identified with in vitro-binding methods, molecular biology techniques, or in vivo-imaging techniques; the latter allow the precise localization of the tumors and their metastases in the patients. Because Somatostatin Receptors in human gastroenteropancreatic tumors are functional, their identification can be used to predict the therapeutical efficacy of octreotide to inhibit excessive hormone release. Of differential diagnostic importance is the fact that other pathological processes in the gastrointestinal tract may be associated with a high density of Somatostatin Receptors. Ninety percent of lymphomas, including those with intestinal involvement express Somatostatin Receptors. Furthermore, a moderate number of colorectal carcinomas contain Somatostatin Receptors, whereas exocrine pancreatic carcinomas do not. Finally, an increased expression of SS Receptors in nonneoplastic conditions, such as in intestinal veins in inflammatory bowel disease, has been recently observed. These observations demonstrate the ability of the human body to regulate SS Receptors in a wide number of tissues and conditions.
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high density of Somatostatin Receptors in veins surrounding human cancer tissue role in tumor host interaction
International Journal of Cancer, 1994Co-Authors: Jean Claude Reubi, Ursula Horisberger, Jean A. LaissueAbstract:Somatostatin Receptors were detected in peritumoral veins of various human cancer tissue specimens. Vascular and neoplastic tissue from 14 colonic adenocarcinomas, 13 carcinoids, 6 renal-cell carcinomas and 7 malignant lymphomas were analyzed for Somatostatin Receptors by use of quantitative receptor autoradiography. In colonic carcinoma specimens, the peritumoral vessels expressed a high density of Somatostatin Receptors, whereas the neoplastic tissue itself was receptor-negative in many cases. In contrast, the incidence and density of Somatostatin Receptors in peritumoral vessels was low in well-differentiated gastrointestinal and bronchial carcinoids, in contrast to the high density of such Receptors in the carcinoid tumor tissue. Autochthonous vessels surrounding other tumors such as renal-cell carcinomas or malignant lymphomas also frequently expressed Somatostatin Receptors. In all cases, the Somatostatin Receptors were localized in veins, particularly in the smooth-muscle cell layer. They exhibited specific and high-affinity binding of Somatostatin-14, Somatostatin-28 and octreotide, suggesting a preferential expression of the SSTR2 receptor subtype. Since the vessels of normal non-neoplastic human tissues, e.g. of intestine or lymphatic organs, have few Somatostatin Receptors, the increased Somatostatin receptor expression in peritumoral vessels observed in this study may be linked to the neoplastic process itself. The results suggest that Somatostatin and Somatostatin Receptors may play a regulatory role for hemodynamic tumor-host interactions, possibly involving tumor stroma generation, tumor environment, angiogenesis and, particularly, vascular drainage of poorly differentiated neoplasms.
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in vitro autoradiographic and in vivo scintigraphic localization of Somatostatin Receptors in human lymphatic tissue
Blood, 1993Co-Authors: Jean Claude Reubi, S. W. J. Lamberts, Ursula Horisberger, B Waser, Eric P Krenning, Janolaf Gebbers, P Gersbach, Jean A. LaissueAbstract:Receptors for the neuropeptide Somatostatin (SS) were evaluated in vitro and in vivo in various human lymphatic tissues, ie, thymus, spleen, and lymph nodes; thymic carcinoids and thymomas were also tested. The Receptors were measured in vitro using receptor autoradiography on tissue sections incubated with the SS analog 125I-[Tyr3]-octreotide or 125I-[Leu8,D-Trp22,Tyr25]-SS-28. All tissues were SS-receptor positive for either radioligand, except the thymomas. In thymic tissue, the Receptors were diffusely located in the medulla, presumably on epithelial cells. In the spleen, the red pulp was strongly labeled. In the lymph nodes, the germinal centers were preferentially labeled. In all tissues, the Receptors were of high affinity (kd thymus, 0.84 nmol/L; kd spleen, 1.6 nmol/L; kd lymph node, 0.62 nmol/L) and specific for SS. Displacement by nanomolar concentrations of SS-14, SS-28, and octreotide was observed, as was guanosine triphosphate dependency. The in vivo visualization of Somatostatin Receptors was performed after injection of 111In-DTPA-octreotide and gamma-camera scintigraphy. The spleen, but not thymus or lymph nodes, were visualized. These data suggest an important role for SS in regulating immune functions through SS Receptors in thymus, spleen, and lymph nodes. Furthermore, SS may regulate neuroendocrine functions in the thymus.
Stefan Schulz - One of the best experts on this subject based on the ideXlab platform.
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Somatostatin Receptors in bronchopulmonary neuroendocrine neoplasms new diagnostic prognostic and therapeutic markers
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Daniel Kaemmerer, Stefan Schulz, Jorg Sanger, Elisa Specht, Ralph M Wirtz, Manal Sayeg, Amelie LuppAbstract:Context and Objectives: Gastroenteropancreatic neuroendocrine neoplasms are known for their overexpression of Somatostatin Receptors (SSTRs), which provide the molecular basis for diagnostic and therapeutic interventions. In contrast, few data on the SSTR expression profile exist for bronchopulmonary neuroendocrine neoplasms (BP-NEN). Design and Settings: A total of 240 formalin-fixed, paraffin-embedded specimens from 26 typical carcinoid (TC), 30 atypical carcinoid (AC), and 34 small cell lung cancer (SCLC) patients were examined retrospectively by immunohistochemistry (IHC) using specific rabbit monoclonal antibodies and evaluated by the immunoreactive score. Adjacent slides from 20 samples of each tumor type were subjected to additional RT-quantitative PCR mRNA analysis. Results: With different expression patterns, SSTRs were present in most of the tumor sections, at both the protein and mRNA levels. The RT-quantitative PCR data correlated with the IHC scores. SSTR1 was detected in approximately 65% of...
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molecular imaging with 68ga sstr pet ct and correlation to immunohistochemistry of Somatostatin Receptors in neuroendocrine tumours
European Journal of Nuclear Medicine and Molecular Imaging, 2011Co-Authors: Daniel Kaemmerer, Stefan Schulz, Luisa Peter, Amelie Lupp, Jorg Sanger, Vikas Prasad, Harshad R Kulkarni, Svenpetter Haugvik, Merten Hommann, Richard P BaumAbstract:Purpose Somatostatin Receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3–5.
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Expression and function of Somatostatin Receptors in peripheral nerve sheath tumors.
Journal of neuropathology and experimental neurology, 2005Co-Authors: Christian Mawrin, Stefan Schulz, Anja Hellwig-patyk, Elmar Kirches, Albert Roessner, Uwe Lendeckel, Raimund Firsching, Christian K. Vorwerk, Gerburg Keilhoff, Knut DietzmannAbstract:Although Somatostatin Receptors have been detected in many normal and neoplastic tissues, little is known of their expression and function in peripheral nerve tumors. In the present study, we examined the expression of all 5 Somatostatin receptor subtypes (sst1-5) in 3 normal peripheral nerves, 3 traumatic neuromas, 27 schwannomas, 18 neurofibromas, and 177 malignant peripheral nerve sheath tumors (MPNSTs) by immunohistochemistry as well as by Western blot and reverse transcriptase-polymerase chain reaction investigations in 2 normal peripheral nerves, one neurofibroma, 5 schwannomas, and 5 MPNSTs. Immunoreactive Somatostatin Receptors were not detectable in normal peripheral nerve and in nonneoplastic Schwann cell proliferations. In contrast, sst2A mRNA and protein was present in 89% of schwannomas. This receptor subtype was less frequently detected in neurofibromas (22%) and MPNSTs (15%). Interestingly, sst4 was seen in 32% of MPNSTs and was almost exclusively expressed in this malignant tumor type. In support of a role in Schwann cell tumor growth control by Somatostatin was the observation of induced internalization of sst2A and inhibition of cell proliferation in an NF1-associated MPNST cell line. Moreover, administration of an sst2A-selective agonist resulted in induction of MPNST cell apoptosis. We conclude that peripheral nerve sheath tumors often express at least one functional Somatostatin receptor. Furthermore, our findings suggest a potential clinical role for Somatostatin receptor agonists in tumor imaging and/or treatment of schwannomas and MPNSTs.
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localization of five Somatostatin Receptors in the rat central nervous system using subtype specific antibodies
Journal of Physiology-paris, 2000Co-Authors: Stefan Schulz, Manuela Händel, Matthias Schreff, Harald Schmidt, Volker HölltAbstract:Abstract The cloning of five members of the Somatostatin receptor family, sst 1 -sst 5 , as well as two isoforms of the Somatostatin receptor 2, sst 2A and sst 2B , enabled us to generate specific anti-peptide antisera against unique sequences in the carboxyl-terminal tail of each Somatostatin receptor subtype. We used these antibodies in multicolor immunofluorescent studies aimed to examine the regional and subcellular distribution of Somatostatin Receptors in adult rat brain. Several findings are notable: The cloned sst 1 receptor is primarily localized to axons, and therefore most likely functions in a presynaptic manner. The cloned sst 2 receptor isoforms exhibit strikingly different distributions, however, both sst 2A and sst 2B are confined to the plasma membrane of neuronal somata and dendrites, and therefore most likely function in a postsynaptic manner. The cloned sst 3 receptor appears to be excluded from ‘classical’ pre- or postsynaptic sites but is selectively targeted to neuronal cilia. The cloned sst 4 receptor is preferentially distributed to distal dendrites, and therefore most likely functions postsynaptically. The cloned sst 5 receptor was not detectable in the adult rat brain, however, prominent sst 5 expression was found in the pituitary. Furthermore, sst 1 -containing axons either co-contained Somatostatin or were closely apposed by Somatostatin-positive terminals in a regional-specific manner. Neuronal somata and dendrites containing either sst 2A , sst 2B or sst 4 were found to exist in close proximity, although not necessarily synaptically linked, to Somatostatin-positive terminals. Together, in the central nervous system the effects of Somatostatin are mediated by several different receptor proteins which are distributed with considerable regional overlap. However, there appears to be a high degree of specialization among Somatostatin receptor subtypes with regard to their subcellular targeting. This subtype-selective targeting may be the underlying principal of organization that allows Somatostatinergic modulation of neuronal activity via both pre- and postsynaptic mechanisms.