Gene Summary

Gene:SSTR1; somatostatin receptor 1
Aliases: SS1R, SS1-R, SRIF-2, SS-1-R
Summary:Somatostatins are peptide hormones that regulate diverse cellular functions such as neurotransmission, cell proliferation, and endocrine signaling as well as inhibiting the release of many hormones and other secretory proteins. Somatostatin has two active forms of 14 and 28 amino acids. The biological effects of somatostatins are mediated by a family of G-protein coupled somatostatin receptors that are expressed in a tissue-specific manner. The protein encoded by this gene is a member of the superfamily of somatostatin receptors having seven transmembrane segments. Somatostatin receptors form homodimers and heterodimers with other members of the superfamily as well as with other G-protein coupled receptors and receptor tyrosine kinases. This somatostatin receptor has greater affinity for somatostatin-14 than -28. [provided by RefSeq, Jul 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:somatostatin receptor type 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: SSTR1 (cancer-related)

Foiani G, Guelfi G, Chiaradia E, et al.
Somatostatin Receptor 2 Expression in Canine Meningioma.
J Comp Pathol. 2019; 166:59-68 [PubMed] Related Publications
The neuropeptide somatostatin (SST) plays an important regulatory role in the proliferation of normal and neoplastic cells. Five subtypes of somatostatin receptors (SSTRs), SSTR1-SSTR5, have been identified in human tumours. The SSTR2 subtype is identified most commonly in meningiomas. Long half-life SST analogues are now recommended for the systemic treatment of unresectable or radiation-refractory recurrent human meningiomas. In this study, SSTR2 expression was evaluated in 46 canine meningiomas; in 21 cases this was by immunohistochemistry and in 25 cases by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). In addition, SSTR2 expression was evaluated by immunocytochemistry, western blotting and RT-qPCR on primary cell cultures prepared from two canine meningiomas. SSTR2 immunohistochemical expression was observed in 17/21 cases (81%), and SSTR2 mRNA expression was detected in 14/25 cases (56%). SSTR2 protein and gene expression were not significantly correlated with the tumour histological subtype or grade. Overall, meningothelial meningiomas showed constant and diffuse SSTR2 immunohistochemical expression and the highest SSTR2 gene expression level compared with other subtypes. A tendency for loss of SSTR2 in high-grade meningiomas was observed in both immunohistochemical and RT-qPCR studies. About 90% of cultured canine meningioma cells showed SSTR2 expression. In both of the meningioma cell cultures, SSTR2 expression was also detected by western blotting and RT-qPCR. This study demonstrates for the first time that canine meningioma expresses SSTR2 and that this expression is maintained in vitro. Our results, while preliminary, provide encouragement for further studies aimed at finding novel medical treatment strategies for canine meningioma, especially for tumours that are not surgically accessible.

Xi T, Zhang G
Integrated analysis of tumor differentiation genes in pancreatic adenocarcinoma.
PLoS One. 2018; 13(3):e0193427 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor differentiation is an important process in the development of cancer. It is valuable to identify key differentiation related genes in the prognosis and therapy of pancreatic adenocarcinoma.
METHODS: The mRNA expression data were downloaded from the Cancer Genome Atlas database. Then, differentially expressed tumor differentiation related genes were identified. Additionally, Gene Ontology functional categories and Kyoto Encyclopedia of Genes and Genomes biochemical pathway was used to explore the function. In addition, receiver operating characteristic and survival analysis were carried out to assess the diagnosis and prognosis value. Finally, the electronic validation of selected tumor differentiation related genes was performed.
RESULTS: A total of 932 genes were identified. Among which, 8 genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA and SSTR1 were differentially expressed in all different tumor differentiation grades. Functional analysis revealed those genes between highly differentiated and other differentiation were remarkably enriched in pancreatic adenocarcinoma and cell cycle pathway. Finally, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, BCL2L1, E2F1 and RAC1 were associated with the survival time of pancreatic adenocarcinoma patient. Among these genes, JUB, ERLIN1, FAM110B, MCM2 and BCL2L1 also had a diagnosis value for pancreatic adenocarcinoma. Additionally, the expression trend of JUB, HMGA2 and MCM2 was increased along with the tumor differentiation grades. And the expression trend of FAM110B was decreased along with the tumor differentiation grades. The electronic validation result was consistent with the bioinformatics analysis.
CONCLUSIONS: 12 tumor differentiation related genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA, SSTR1, BCL2L1, E2F1, RAC1 and STAT1 played crucial roles in the differentiation of pancreatic adenocarcinoma.

Yu J, To KF, Liang QY
Epstein-Barr virus-driven promoter hypermethylated genes in gastric cancer.
Hong Kong Med J. 2017; 23 Suppl 5(4):17-22 [PubMed] Related Publications

Pedraza-Arévalo S, Hormaechea-Agulla D, Gómez-Gómez E, et al.
Somatostatin receptor subtype 1 as a potential diagnostic marker and therapeutic target in prostate cancer.
Prostate. 2017; 77(15):1499-1511 [PubMed] Related Publications
BACKGROUND: Prostate cancer (PCa) is a highly prevalent neoplasia that is strongly influenced by the endocrine system. Somatostatin (SST) and its five receptors (sst1-5 encoded by SSTR1-5 genes) comprise a pleiotropic system present in most endocrine-related cancers, some of which are successfully treated with SST analogs. Interestingly, it has been reported that SSTR1 is overexpressed in PCa, but its regulation, functional role, and clinical implications are still poorly known.
METHODS: PCa specimens (n = 52) from biopsies and control prostates from cystoprostatectomies (n = 12), as well as in silico databases were used to evaluate SSTR1 and miRNAs expression. In vitro studies in 22Rv1 PCa cells were implemented to explore the regulation of SSTR1/sst1 by different miRNAs, and to evaluate the consequences of SSTR1/sst1 overexpression, silencing and/or activation [with the specific BIM-23926 sst1 agonist (IPSEN)] on cell-proliferation, migration, signaling-pathways, and androgen-signaling.
RESULTS: We found that SSTR1 is overexpressed in multiple cohorts of PCa samples, as compared with normal prostate tissues, wherein it correlates with androgen receptor (AR) expression, and appears to be associated with aggressiveness (metastasis). Furthermore, our data revealed that SSTR1/sst1 expression might be regulated by specific miRNAs in PCa, including miR-24, which is downregulated in PCa samples and correlates inversely with SSTR1 expression. In vitro studies indicated that treatment with the BIM-23926 sst1 agonist, as well as SSTR1 overexpression, decreased, whereas SSTR1 silencing increased, cell-proliferation in 22Rv1 cells, likely through the regulation of PI3K/AKT-CCND3 signaling-pathway. Importantly, sst1 action was also able to modulate androgen/AR activity, and reduced PSA secretion from PCa cell lines.
CONCLUSIONS: Altogether, our results indicate that SSTR1 is overexpressed in PCa, where it can exert a relevant pathophysiological role by decreasing cell-proliferation and PSA secretion. Therefore, sst1, possibly in combination with miR-24, could be used as a novel tool to explore therapeutic targets in PCa.

Modarai SR, Opdenaker LM, Viswanathan V, et al.
Somatostatin signaling via SSTR1 contributes to the quiescence of colon cancer stem cells.
BMC Cancer. 2016; 16(1):941 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neuroendocrine cells (NECs) reside adjacent to colonic stem cells (SCs) in the crypt stem cell (SC) niche, but how NECs are involved in regulation of SCs is unclear. We investigated NECs expressing somatostatin (SST) and somatostatin receptor type 1 (SSTR1) because SST inhibits intestinal proliferation.
HYPOTHESIS: SSTR1 cells maintain SCs in a quiescent state, and aberrant SST signaling contributes to SC overpopulation in colorectal cancer (CRC).
METHODS: The proportion of SCs to NECs cells was quantified, by flow cytometry, in CRC cell lines and primary normal/tumor tissues based on cellular ALDH and SSTR1 levels, respectively. Doubling time and sphere-formation was used to evaluate cell proliferation and stemness. CRC cell lines were treated with exogenous SST and SST inhibitor cyclosomatostatin (cycloSST) and analyzed for changes in SCs and growth rate. Paracrine signaling between NECs and SCs was ascertained using transwell cultures of ALDH+ and SSTR1+ cells.
RESULTS: In CRC cell lines, the proportion of ALDH+ cells inversely correlates with proportion of SSTR1+ cells and with rate of proliferation and sphere-formation. While primary normal tissue shows SST and SSTR1 expression, CRC shows only SSTR1 expression. Moreover, ALDH+ cells did not show SST or SSTR1 expression. Exogenous SST suppressed proliferation but not ALDH+ population size or viability. Inhibition of SSTR1 signaling, via cycloSST treatment, decreased cell proliferation, ALDH+ cell population size and sphere-formation. When co-cultured with SSTR1+ cells, sphere-formation and cell proliferation of ALDH+ cells was inhibited.
CONCLUSION: That each CRC cell line has a unique ALDH+/SSTR1+ ratio which correlates with its growth dynamics, suggests feedback mechanisms exist between SCs and NECs that contribute to regulation of SCs. The growth suppression by both SST and cycloSST treatments suggests that SST signaling modulates this feedback mechanism. The ability of SSTR1+ cells to decrease sphere formation and proliferation of ALDH+ cells in transwell cultures indicates that the ALDH subpopulation is regulated by SSTR1 via a paracrine mechanism. Since ALDH+ cells lack SST and SSTR1 expression, we conjecture that SST signaling controls the rate of NEC maturation as SCs mature along the NEC lineage, which contributes to quiescence of SCs and inhibition of proliferation.

Qian ZR, Li T, Ter-Minassian M, et al.
Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors.
Pancreas. 2016; 45(10):1386-1393 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET.
METHODS: Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders.
RESULTS: High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs.
CONCLUSIONS: Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.

Drastikova M, Beranek M, Gabalec F, et al.
Expression profiles of somatostatin, dopamine, and estrogen receptors in pituitary adenomas determined by means of synthetic multilocus calibrators.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016; 160(2):238-43 [PubMed] Related Publications
AIMS: Pituitary adenomas (PA) are non-invasive benign tumors with a high autopsy prevalence. They are classified according to the type of hormone secreted (prolactin, growth hormone, adrenocorticotropin, thyrotropin, folitropin, or luteinizing hormone). Clinically non-functioning adenomas (CNFA) lacking the typical hypersecretion of hormones make up a significant portion of PA. The aim of the study was to determine the complete expression profiles of somatostatin receptors (SSTR1-SSTR5), dopamine receptors type 2 (D2R), and estrogen receptors (ER1) in various types of PA.
METHODS: Adenoma specimens were obtained from 206 patients during transsphenoidal resection. For quantitative analysis, reverse transcription and consequent real-time PCR with synthetic multilocus calibrators (SMC) were used. The obtained data were normalized to the number of transcripts of the beta-glucuronidase gene.
RESULTS: The use of SMC enabled the alignment of individual calibration functions for all the receptors. No relationships between the expression of the receptors and the tumor size, site of extension, gender or age at diagnosis were significant. In growth hormone-secreting adenomas, D2R and SSTR2 transcripts were extensively expressed, followed by ER1, SSTR5, SSTR3, and SSTR1. In patients with macroprolactinomas, transsphenoidal resection was indicated because dopamine agonists did not normalize prolactin levels. D2R, ER1 and SSTR1 transcripts were significantly transcribed. Corticotroph adenomas showed high levels of D2R and ER1 transcripts and lower amounts of SSTR2 and SSTR1 transcripts. SSTR5 transcripts were very low. Subjects with CNFA dominantly expressed D2R and ER1, followed by SSTR2 and SSTR3 mRNA.
CONCLUSION: We evaluated SSTR1-SSTR5, D2R, and ER1 expressions in a large group of pituitary adenomas and we found that determining their individual expression profiles could help when choosing the optimal postoperative treatment.

Tolkach Y, Merseburger A, Herrmann T, et al.
Signatures of Adverse Pathological Features, Androgen Insensitivity and Metastatic Potential in Prostate Cancer.
Anticancer Res. 2015; 35(10):5443-51 [PubMed] Related Publications
BACKGROUND/AIM: The genetic characterization of prostate tumors is important for personalized therapy. The aim of the present study was to investigate the role of previously described prostate cancer-related genes in the genetic characterization of prostate tumors.
MATERIALS AND METHODS: Forty-two genes were selected for expression analysis (real time-quantitative polymerase chain reaction). One normal prostatic epithelial cell line and three standardized prostate cancer cell lines were used. Twenty-eight patients treated with radical prostatectomy were included in the study.
RESULTS: The following genes appeared to be possibly related to the metastatic potential of the tumor: ELOVL fatty acid elongase 7 (ELOVL7), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), gastrulation brain homeobox 2 (GBX2), golgi membrane protein 1 (GOLM1), homeobox C6 (HOXC6), minichromosome maintenance complex component 6 (MCM6), marker of proliferation Ki-67 (MKI67), mucin 1, cell surface associated (MUC1), MYC binding protein 2, E3 ubiquitin protein ligase (MYCBP2), somatostatin receptor 1 (SSTR1), topoisomerase (DNA) II alpha 170 kDa (TOP2A) and exportin 6 (XPO6). Six genes were differentially expressed in patients with localized and locally advanced cancer (GOLM1, GBX2, XPO6, SSTR1, TOP2A and cell division cycle associated 5, CDCA5) and three genes (HOXC6, Cyclin-dependent kinase inhibitor 2A (CDKN2A) and MYC binding protein 2, E3 ubiquitin protein ligase, MYCBP2) in patients with a low vs. high Gleason grade/sum.
CONCLUSION: Some of the investigated genes show promising prognostic and classification features, which might be useful in a clinical setting, warranting for further validation.

Kiseljak-Vassiliades K, Xu M, Mills TS, et al.
Differential somatostatin receptor (SSTR) 1-5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors.
Mol Cell Endocrinol. 2015; 417:73-83 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The aim of this study was to examine whether differential expression of somatostatin receptors (SSTR) 1-5 and downstream effectors are different in densely (DG) and sparsely (SG) granulated histological growth hormone (GH) pituitary tumor subtypes.
METHODS: The study included 33 acromegalic patients with 23 DG and 10 SG tumors. SSTR1-5 were measured by qPCR and immunoblotting. Signaling candidates downstream of SSTR2 were also assessed.
RESULTS: SSTR2 mRNA and protein levels were significantly higher in DG compared to SG tumors. Downstream of SSTR2, p27(kip1) was decreased (2.6-fold) in SG compared to DG tumors, suggesting a potential mechanism of SSA resistance in SG tumors with intact SSTR2 expression. Re-expression of E-cadherin in GH pituitary cell increased p27(kip1) levels.
CONCLUSIONS: Histological subtyping correlated with SSTR2, E cadherin and p27(kip) protein levels and these may serve as useful biomarkers in GH tumors to predict behavior and response to therapy with SSA.

Kaemmerer D, Träger T, Hoffmeister M, et al.
Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy.
Oncotarget. 2015; 6(29):27566-79 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC).
METHODS: SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21-49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data.
RESULTS: Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors.
CONCLUSION: We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.

Kool MM, Galac S, van der Helm N, et al.
Expression of somatostatin, dopamine, progesterone and growth hormone receptor mRNA in canine cortisol-secreting adrenocortical tumours.
Vet J. 2015; 206(1):108-10 [PubMed] Related Publications
Cortisol-secreting adrenocortical tumours (AT) in dogs are characterised by uncontrolled growth and excessive cortisol secretion. Dysregulated hormone receptor expression might be involved in tumour growth and hypersecretion of cortisol. The relative mRNA expression of growth hormone receptor, progesterone receptor, somatostatin receptors (SSTR1-3) and dopamine receptors (DRD1-2 and DRD5) was evaluated in 36 canine ATs and 15 adrenal glands obtained from healthy dogs. Compared with normal adrenal tissue, DRD2 mRNA expression was relatively lower in carcinomas, while SSTR1 mRNA expression was lower in both adenomas and carcinomas. Both of these features might contribute to loss of inhibition of tumour growth and upregulation of cortisol secretion. In canine ATs that had recurred within 30 months of surgical adrenalectomy, a marked increase in expression of DRD1 mRNA was observed. Targeting of specific hormone receptors, expressed by ATs, might be exploited for therapy.

Bodei L, Kidd M, Modlin IM, et al.
Gene transcript analysis blood values correlate with ⁶⁸Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status.
Eur J Nucl Med Mol Imaging. 2015; 42(9):1341-52 [PubMed] Related Publications
PURPOSE: Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between (68)Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs.
METHODS: We utilized two independent patient groups with positive (68)Ga-SSA PET: data set 1 ((68)Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 ((68)Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUVmax), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships.
RESULTS: SUVmax measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ(2) = 20.1, p < 2.5×10(-6)). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUVmax (R (2) = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUVmax. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUVmax [ROC-derived AUC (R (2) = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters was evident.
CONCLUSION: (68)Ga-SSA PET imaging parameters (SUVmax) correlated with a circulating NET transcript signature. Disease status could be predicted by an elevated quotient of gene expression (MORF4L2) and SUVmax. These observations provide the basis for further exploration of strategies that combine imaging parameters and disease-specific molecular data for the improvement of NET management.

Xu C, Zhang H
Somatostatin receptor based imaging and radionuclide therapy.
Biomed Res Int. 2015; 2015:917968 [PubMed] Free Access to Full Article Related Publications
Somatostatin (SST) receptors (SSTRs) belong to the typical 7-transmembrane domain family of G-protein-coupled receptors. Five distinct subtypes (termed SSTR1-5) have been identified, with SSTR2 showing the highest affinity for natural SST and synthetic SST analogs. Most neuroendocrine tumors (NETs) have high expression levels of SSTRs, which opens the possibility for tumor imaging and therapy with radiolabeled SST analogs. A number of tracers have been developed for the diagnosis, staging, and treatment of NETs with impressive results, which facilitates the applications of human SSTR subtype 2 (hSSTr2) reporter gene based imaging and therapy in SSTR negative or weakly positive tumors to provide a novel approach for the management of tumors. The hSSTr2 gene can act as not only a reporter gene for in vivo imaging, but also a therapeutic gene for local radionuclide therapy. Even a second therapeutic gene can be transfected into the same tumor cells together with hSSTr2 reporter gene to obtain a synergistic therapeutic effect. However, additional preclinical and especially translational and clinical researches are needed to confirm the value of hSSTr2 reporter gene based imaging and therapy in tumors.

Kanakis G, Grimelius L, Spathis A, et al.
Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role.
Neuroendocrinology. 2015; 101(3):211-22 [PubMed] Related Publications
OBJECTIVE: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs).
METHODS: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR.
RESULTS: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription.
CONCLUSIONS: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

Misawa K, Misawa Y, Kondo H, et al.
Aberrant methylation inactivates somatostatin and somatostatin receptor type 1 in head and neck squamous cell carcinoma.
PLoS One. 2015; 10(3):e0118588 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The aim of this study was to define somatostatin (SST) and somatostatin receptor type 1 (SSTR1) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker.
METHODS: Gene expression was measured by quantitative RT-PCR. Promoter methylation status was determined by quantitative methylation-specific PCR (Q-MSP) in HNSCC.
RESULTS: Methylation was associated with transcription inhibition. SST methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040). SSTR1 hypermethylation in 64% of cases was correlated with tumor size (P = 0.037), stage (P = 0.037), SST methylation (P < 0.001), and expression of galanin (P = 0.03), GALR2 (P = 0.014), TAC1 (P = 0.023), and tachykinin receptor type 1 (TACR1) (P = 0.003). SST and SSTR1 promoter hypermethylation showed highly discriminating receiver operator characteristic curve profiles, which clearly distinguished HNSCC from adjacent normal mucosal tissues. Concurrent hypermethylation of galanin and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.0001). Among patients with oral cavity and oropharynx cancer, methylation of both SST and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.028). In multivariate logistic-regression analysis, concomitant methylation of galanin and SSTR1 was associated with an odds ratio for recurrence of 12.53 (95% CI, 2.62 to 59.8; P = 0.002).
CONCLUSIONS: CpG hypermethylation is a likely mechanism of SST and SSTR1 gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker.

Gabalec F, Drastikova M, Cesak T, et al.
Dopamine 2 and somatostatin 1-5 receptors coexpression in clinically non-functioning pituitary adenomas.
Physiol Res. 2015; 64(3):369-77 [PubMed] Related Publications
This study investigated quantitated expression of dopamine 2 receptor (D2R) and somatostatin receptors of the five types (SSTR1-SSTR5) in a large series of clinically non-functioning pituitary adenomas (CNFAs). Co-expression of these receptors in individual adenomas was studied as well as correlation between receptor types. Adenoma tissue from 198 patients who underwent surgery for CNFAs was analyzed by immunohistochemistry and quantitative real-time PCR. D2R and SSTR1-3 mRNA was expressed in all 198 adenomas. SSTR4 and SSTR5 were detectable in 85 % and 61 % of adenomas, respectively. Expression of D2R was significantly higher than that of the somatostatin receptors. The median relative expressions were as follows from highest D2R > SSTR3 > SSTR2 > SSTR1 > SSTR5 > SSTR4. High relative expression (ratio to beta-glucuronidase mRNA > 1) of D2R was found in 60 % of tumors, high expression of SSTR1 in 7.5 %, SSTR2 in 7 %, SSTR3 in 4 % and SSTR5 in 0.5 %. The quantity of D2R correlated positively with expression of SSTR2 and SSTR3, and negatively with SSTR1 and SSTR5. Among histological adenoma types, SSTR1 was significantly higher in null-cell adenomas and SSTR3 was lower in silent corticotroph adenomas. In conclusions, in CNFAs, high expression of somatostatin receptors is much less common than that of D2R, and co-expression of both these receptors is exceptional. D2R and SSTR3 seem to be the most promising targets for pharmacological treatment.

Murasawa S, Kageyama K, Sugiyama A, et al.
Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo.
Mol Cell Endocrinol. 2014; 394(1-2):37-46 [PubMed] Related Publications
Adrenocorticotropic hormone (ACTH) production by pituitary corticotroph adenomas is the main cause of Cushing's disease. A drug that targets pituitary ACTH-secreting adenomas would aid treatment of Cushing's disease. Octreotide, a somatostatin receptor type 2 (SSTR2)-preferring somatostatin analogue, has no effect on ACTH secretion in patients with Cushing's disease. The multiligand SOM230 (pasireotide) displays a much higher affinity for SSTR1 and SSTR5 than octreotide and suppresses ACTH secretion in cultures of human corticotroph tumors to a greater extent than octreotide. In the present in vitro and in vivo study, we determined the effect of SOM230 on ACTH production and cell proliferation of AtT-20 corticotroph tumor cells. SOM230 decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and ACTH levels in the culture medium of these cells, suggesting that SOM230 suppresses ACTH synthesis and secretion in corticotroph tumor cells. SOM230 also decreased cell proliferation and both cyclic adenosine monophosphate response element-binding protein and Akt phosphorylation in AtT-20 cells. SSTR5 knockdown inhibited the SOM230-induced decreases in cell proliferation. Fluorescence-activated cell sorting analyses revealed that SOM230 did not attenuate cell cycle progression. Tumor weight in mice xenografted with AtT-20 cells and treated with SOM230 was significantly lower than in AtT-20-xenografted control mice. SOM230 also significantly decreased plasma ACTH levels, and POMC and pituitary tumor transforming gene mRNA levels in the tumor cells. Thus, SOM230 inhibits ACTH production and corticotroph tumor cell proliferation in vitro and in vivo.

Wang S, Bao Z, Liang QM, et al.
Octreotide stimulates somatostatin receptor-induced apoptosis of SW480 colon cancer cells by activation of glycogen synthase kinase-3β, A Wnt/β-catenin pathway modulator.
Hepatogastroenterology. 2013; 60(127):1639-46 [PubMed] Related Publications
BACKGROUND/AIMS: Peptide hormone somatostatin and its receptors (SSTRs) have a wide range of physiological functions and play a role in the treatment of numerous human diseases, including colorectal cancer. Octreotide, a somatostatin-analog peptide, inhibits growth of colonic cancer SW480 cells through Wnt/β-catenin pathway modulation. However, the specific octreotide-stimulating SSTR subtypes and the signal-transduction mechanism responsible for the negative regulation of Wnt/β-catenin pathway by octreotide have not been fully elucidated.
METHODOLOGY: Octreotide-induced apoptosis in SW480 colon cancer cells mediated by SSTR2,SSTR5-dependent regulation of the Wnt/β-catenin pathway components GSK-3β and β-catenin was investigated. Cell apoptosis of SW480 cells was measured by apoptosis-DNA ladder assay. SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 mRNA expression levels were confirmed by RT-PCR; β-catenin, TCF-4, cyclin D1, c-Myc, and GSK-3β protein levels were examined by Western blot. The distribution of β-catenin in the cell was analyzed with immunocytochemistry.
RESULTS: Octreotide treatment increased SSTR2,SSTR5-induced apoptosis of SW480 colon cancer cells, promoted the plasma membrane accumulation of β-catenin, inactivated T-cell factor-dependent transcription, and downregulated Wnt target genes cyclin D1 and c-Myc. Further, octreotide treatment mediated the activation of GSK-3.
CONCLUSIONS: These preliminary findings showed the negative regulation of the Wnt/β-catenin pathway by peptide hormone G protein-coupled receptors SSTRs.

Ruscica M, Magni P, Steffani L, et al.
Characterization and sub-cellular localization of SS1R, SS2R, and SS5R in human late-stage prostate cancer cells: effect of mono- and bi-specific somatostatin analogs on cell growth.
Mol Cell Endocrinol. 2014; 382(2):860-70 [PubMed] Related Publications
Somatostatin (SST) and SST receptors (SS1R, SS2R, SS3R, SS4R and SS5R) appear to play a significant role in the progression of human prostate cancer (PCa), which is associated with heterogeneity of SSRs expression and specific cell localization as we already demonstrated in the LNCaP cell line, an in vitro model of human androgen-dependent PCa. In this study, PC-3 and DU-145 human castration-resistant PCa cells were found to express all SSRs, while LNCaP expressed all but SS4R. A 48-h treatment with BIM-23244 (SS2R/SS5R) or BIM-23926 (SS1R) SST analogs was more effective in inhibiting cell proliferation, compared to BIM-23120 (SS2R), BIM-23206 (SS5R) and BIM-23704 (SS1R/SS2R). BIM-23926 (SS1R) treatment increased the amount of p21 and decreased phosphorylated (p) ERK1/2. BIM-23244 (SS2R/SS5R) led to p21 increment only in PC-3 cells, and to pERK1/2 reduction in both cell lines. SS1R/SS2R and SS2R/SS5R receptor dimers were natively present on cell membrane and their amount was increased by BIM-23704 (SS1R/SS2R) or BIM-23244 (SS2R/SS5R) treatment, respectively. SS1R, SS2R and SS5R were differently distributed among nuclear, lysosomal and microsomal compartment, according to their different recycling dynamics. These results show that, in PC-3, DU-145 and LNCaP cells, activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effects.

Vieria Neto L, Wildemberg LE, Colli LM, et al.
ZAC1 and SSTR2 are downregulated in non-functioning pituitary adenomas but not in somatotropinomas.
PLoS One. 2013; 8(10):e77406 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: There are few data regarding ZAC1 expression in clinically non-functioning pituitary adenomas (NFPA). Because somatotropinomas and NFPA behave differently with respect to tumor shrinkage during somatostatin analogs (SA) therapy, we sought to compare the ZAC1 and somatostatin receptor (sstr) types 1, 2, 3 and 5 mRNA expression in these two pituitary adenoma subtypes and in normal human pituitaries.
METHODS: ZAC1 and SSTR mRNA expression levels were evaluated using real-time RT-PCR (TaqMan) in 20 NFPA and compared with the expression levels in 23 somatotropinomas and five normal pituitaries. The NFPA invasiveness was evaluated using magnetic resonance imaging with Hardy's modified criteria. Ki-67 and p53 were evaluated using immunohistochemistry.
RESULTS: A total of 20 patients with NFPA [6 males, median age 56 years (range: 30-78)], 23 with acromegaly [12 males, median age 43 years (range: 24-57)] and five normal pituitaries [4 males, median age 48 years (range: 36-54)] were included. Four of the patients (20%) had Hardy's grade 2 tumors; all of the others had Hardy's grade 3 tumors. The Ki-67 median expression was 2.35 (range: 0.2-9.23), and only four of the tumors (20%) were positive for p53. The ZAC1 mRNA expression was significantly lower in NFPA than in somatotropinomas and in normal pituitaries (p<0.001 for both), as well as the SSTR2 (p=0.001 and 0.01, respectively). The SSTR3 expression was higher in the NFPA than in the somatotropinomas and in the normal pituitaries (p=0.03 and 0.02, respectively). No correlation was found between the ZAC1 mRNA expression and the tumor invasiveness, Ki-67 and p53.
CONCLUSION: ZAC1 and SSTR2 are underexpressed and SSTR3 is overexpressed in NFPA compared to those in somatotropinomas and in normal pituitaries, which might explain the lack of tumor shrinkage that is observed in response to commercially available SA therapy in patients with NFPA.

Mayr B, Buslei R, Theodoropoulou M, et al.
Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas.
Eur J Endocrinol. 2013; 169(4):391-400 [PubMed] Related Publications
OBJECTIVE: GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level.
METHODS: In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.
RESULTS: The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%).
CONCLUSIONS: Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.

Zhao J, Liang Q, Cheung KF, et al.
Somatostatin receptor 1, a novel EBV-associated CpG hypermethylated gene, contributes to the pathogenesis of EBV-associated gastric cancer.
Br J Cancer. 2013; 108(12):2557-64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatostatin receptor 1 (SSTR1) was preferentially methylated in Epstein-Barr virus (EBV)-positive gastric cancer using promoter methylation array. We aimed to analyse the epigenetic alteration and biological function of SSTR1 in EBV-associated gastric cancer (EBVaGC).
METHODS: Promoter methylation was examined by combined bisulphite restriction analysis (COBRA) and pyrosequencing. The biological functions of SSTR1 were evaluated by loss- and gain-of-function assays.
RESULTS: Promoter hypermethylation of SSTR1 was detected in EBV-positive gastric cancer cell lines (AGS-EBV) with SSTR1 transcriptional silence, but not in EBV-negative gastric cancer cell lines with SSTR1 expression. Expression level of SSTR1 was restored in AGS-EBV by exposure to demethylating agent. Moreover, methylation level of SSTR1 was significantly higher in EBV-positive primary gastric cancers compared with EBV-negative gastric cancers (P=0.004). Knock-down of SSTR1 in gastric cancer cell lines (AGS and BGC823) increased cell proliferation and colony formation ability, and promoted G1 to S-phase transition, enhanced cell migration and invasive ability. In contrast, ectopic expression of SSTR1 in gastric cancer cell lines (MKN28 and MGC803) significantly suppressed cell growth in culture conditions and reduced tumour size in nude mice. The tumour suppressive effect of SSTR1 was associated with upregulation of cyclin-dependent kinase inhibitors (p16, p15, p27 and p21); downregulation of oncogenes (MYC and MDM2), key cell proliferation and pro-survival regulators (PI3KR1, AKT, BCL-XL and MET); and inhibition of the migration/invasion-related genes (integrins, MMP1 (matrix metallopeptidase 1), PLAUR (plasminogen activator urokinase receptor) and IL8 (interleukin 8)).
CONCLUSION: Somatostatin receptor 1 is a novel methylated gene driven by EBV infection in gastric cancer cells and acts as a potential tumour suppressor.

Niesen CE, Xu J, Fan X, et al.
Transcriptomic profiling of human peritumoral neocortex tissues revealed genes possibly involved in tumor-induced epilepsy.
PLoS One. 2013; 8(2):e56077 [PubMed] Free Access to Full Article Related Publications
The molecular mechanism underlying tumor-induced epileptogenesis is poorly understood. Alterations in the peritumoral microenvironment are believed to play a significant role in inducing epileptogenesis. We hypothesize that the change of gene expression in brain peritumoral tissues may contribute to the increased neuronal excitability and epileptogenesis. To identify the genes possibly involved in tumor-induced epilepsy, a genome-wide gene expression profiling was conducted using Affymetrix HG U133 plus 2.0 arrays and RNAs derived from formalin-fixed paraffin embedded (FFPE) peritumoral cortex tissue slides from 5-seizure vs. 5-non-seizure low grade brain tumor patients. We identified many differentially expressed genes (DEGs). Seven dysregulated genes (i.e., C1QB, CALCRL, CCR1, KAL1, SLC1A2, SSTR1 and TYRO3) were validated by qRT-PCR, which showed a high concordance. Principal Component Analysis (PCA) showed that epilepsy subjects were clustered together tightly (except one sample) and were clearly separated from the non-epilepsy subjects. Molecular functional categorization showed that significant portions of the DEGs functioned as receptor activity, molecular binding including enzyme binding and transcription factor binding. Pathway analysis showed these DEGs were mainly enriched in focal adhesion, ECM-receptor interaction, and cell adhesion molecules pathways. In conclusion, our study showed that dysregulation of gene expression in the peritumoral tissues may be one of the major mechanisms of brain tumor induced-epilepsy. However, due to the small sample size of the present study, further validation study is needed. A deeper characterization on the dysregulated genes involved in brain tumor-induced epilepsy may shed some light on the management of epilepsy due to brain tumors.

Arne G, Nilsson B, Dalmo J, et al.
Gastrointestinal stromal tumors (GISTs) express somatostatin receptors and bind radiolabeled somatostatin analogs.
Acta Oncol. 2013; 52(4):783-92 [PubMed] Related Publications
BACKGROUND: Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptor-mediated radiotherapy (PRRT).
MATERIAL AND METHODS: Expression profiling of SSTR1-5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy ((111)In-octreotide) and measurement of (111)In activity in tumor specimens was performed in seven patients. Uptake and internalization of (177)Lu- octreotate was studied in primary cell cultures from two patients.
RESULTS: Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3-5 were expressed at low levels. Immunohistochemical analysis confirmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3-5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using (111)In-octreotide, demonstrated tumor uptake of (111)In in three of six GIST patients. Measurement of (111)In activity in excised tumor specimens from five patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifically bound and internalized (177)Lu when incubated with the therapeutic compound (177)Lu-octreotate for 4-48 hours (p < 0.05).
CONCLUSION: Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.

Zhao J, Liang Q, Cheung KF, et al.
Genome-wide identification of Epstein-Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells.
Cancer. 2013; 119(2):304-12 [PubMed] Related Publications
BACKGROUND: Aberrant methylation of tumor-related genes has been reported in Epstein-Barr virus (EBV)-associated gastric cancers. This study sought to profile EBV-driven hypermethylation in EBV-infected cells.
METHODS: The EBV-positive AGS gastric cancer cell line (AGS-EBV) and EBV-negative AGS cells were used in this study. DNA methyltransferase-3b (DNMT3b) activity was assessed by EpiQuick activity assay, and genome-wide DNA methylation profiles were assessed by methyl-DNA immunoprecipitation microarray assay.
RESULTS: EBV infection was confirmed in AGS-EBV cells by EBV-encoded RNA in situ hybridization. Expression and activity of DNA methyltransferase-3b (DNMT3b) was significantly increased in AGS-EBV compared to AGS. Ectopic expression of LMP2A (latent membrane protein 2A) in AGS increased activity of DNMT3b. A total of 1065 genes were differentially methylated by EBV infection (fold-changes ≥ 2, P < .05) in AGS-EBV compared to AGS cells. The majority of the differentially methylated genes (83.2%, 886 of 1065 genes) had cytosine-guanine dinucleotide (CpG) hypermethylation in AGS-EBV (fold-changes 2.43∼65.2) versus that found in AGS cells. Gene ontology analysis revealed that hypermethylated genes were enriched in the important cancer pathways (≥ 10 genes each, P ≤ .05) including mitogen-activated protein kinase signaling, cell adhesion molecules, wnt signaling pathway, and so forth. Six novel hypermethylated candidates (IL15RA, REC8, SSTR1, EPHB6, MDGA2, and SCARF2) were further validated. Higher levels of DNA methylation were confirmed for all these genes in AGS-EBV cells by bisulfite genomic sequencing. Furthermore, these candidates were silenced or down-regulated in AGS-EBV cells, but can be restored by demethylation treatment.
CONCLUSIONS: EBV infection in AGS cells induced aberrant CpG hypermethylation of 886 genes involving in important cancer-related pathways. Induction of promoter methylation by EBV is regulated by up-regulation of DNMT3b through LMP2A.

Franko-Tobin LG, Mackey LV, Huang W, et al.
Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics.
Oncologist. 2012; 17(2):220-32 [PubMed] Free Access to Full Article Related Publications
The role of Notch signaling in cervical cancer is seemingly controversial. To confirm the function of Notch signaling in this type of cancer, we established a stable Notch1-activated cervical cancer HeLa cell line. We found that Notch1 activation resulted in apoptosis, cell cycle arrest, and tumor suppression. At the molecular level, we found that a variety of genes associated with cyclic AMP, G protein-coupled receptor, and cancer signaling pathways contributed to Notch1-mediated tumor suppression. We observed that the expression of somatostatin (SST) was dramatically induced by Notch1 signaling activation, which was accompanied by enhanced expression of the cognate SST receptor subtype 1 (SSTR1) and SSTR2. Certain genes, such as tumor protein 63 (TP63, p63), were upregulated, whereas others, such as B-cell lymphoma 2 (BCL-2), Myc, Akt, and STAT3, were downregulated. Subsequently, knockdown of Notch1-induced SST reversed Notch1-induced decrease of BCL-2 and increase of p63, indicating that Notch1-induced tumor suppression may be partly through upregulating SST signaling. Our findings support a possible crosstalk between Notch signaling and SST signaling. Moreover, Notch-induced SSTR activation could enhance SSTR-targeted cancer chemotherapy. Valproic acid (VPA), a histone deacetylase inhibitor, suppressed cell growth and upregulated the expression of Notch1 and SSTR2. A combination therapy with VPA and the SSTR2-targeting cytotoxic conjugate CPT-SST strongly led to greater suppression, as compared to each alone. Our findings thus provide us with a promising clinical opportunity for enhanced cancer therapy using combinations of Notch1-activating agents and SSTR2-targeting agents.

Dalezis P, Geromichalos GD, Trafalis DT, et al.
Dexamethasone plus octreotide regimen increases anticancer effects of docetaxel on TRAMP-C1 prostate cancer model.
In Vivo. 2012 Jan-Feb; 26(1):75-86 [PubMed] Related Publications
AIM: The aim of this study was to evaluate whether the neoadjuvant use of the dexamethasone (DEX) plus octreotide (OCT) regimen can improve the direct anticancer effects of docetaxel (DOC) in the TRAMP-C1 prostate cancer model.
MATERIALS AND METHODS: TRAMP-C1 cells were first characterized for the expression of SSTR1-5 and then were inoculated onto the femur of C57Bl mice. Investigation protocols employed TRAMP-C1 cell proliferation and invasion assays, analysis of radiographic images of the bone lesions and overall survival of the diseased animals.
RESULTS: The triple combination treatment scheme showed significant anticancer effects, in both proliferation and invasion assays, compared to any single agent treatment scheme. DOC treatment following the neoadjuvant administration of DEX plus OCT regimen improved significantly the anticancer effects both on the grading of the bone lesions and on the overall survival of the diseased animals.
CONCLUSION: Our data suggest that the neoadjuvant administration of DEX plus OCT regimen can improve the anticancer effects of DOC on the TRAMP-C1 model.

Li H, Bitler BG, Vathipadiekal V, et al.
ALDH1A1 is a novel EZH2 target gene in epithelial ovarian cancer identified by genome-wide approaches.
Cancer Prev Res (Phila). 2012; 5(3):484-91 [PubMed] Free Access to Full Article Related Publications
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. EZH2 silences gene expression through trimethylating lysine 27 on histone H3 (H3K27Me3). EZH2 is often overexpressed in EOC and has been suggested as a target for EOC intervention. However, EZH2 target genes in EOC remain poorly understood. Here, we mapped the genomic loci occupied by EZH2/H3K27Me3 using chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and globally profiled gene expression in EZH2-knockdown EOC cells. Cross-examination of gene expression and ChIP-seq revealed a list of 60 EZH2 direct target genes whose expression was upregulated more than 1.5-fold upon EZH2 knockdown. For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. Furthermore, the presence of H3K27Me3 at the genomic loci of these EZH2 target genes was dependent upon EZH2. Interestingly, expression of ALDH1A1, a putative marker for EOC stem cells, was significantly downregulated in high-grade serous EOC (n = 53) compared with ovarian surface epithelial cells (n = 10, P < 0.001). Notably, expression of ALDH1A1 negatively correlated with expression of EZH2 (n = 63, Spearman r = -0.41, P < 0.001). Thus, we identified a list of 60 EZH2 target genes and established that ALDH1A1 is a novel EZH2 target gene in EOC cells. Our results suggest a role for EZH2 in regulating EOC stem cell equilibrium via regulation of ALDH1A1 expression.

Kaemmerer D, Peter L, Lupp A, et al.
Molecular imaging with ⁶⁸Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours.
Eur J Nucl Med Mol Imaging. 2011; 38(9):1659-68 [PubMed] Related Publications
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.
METHODS: Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative (68)Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV(max) and SUV(mean)) were used for PET/CT.
RESULTS: The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV(max) on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV(mean) (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading.
CONCLUSION: The highly significant correlation between SSTR2A and SSTR5 and the SUV(max) on the (68)Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of (68)Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using (68)Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy.

Muscarella LA, D'Alessandro V, la Torre A, et al.
Gene expression of somatostatin receptor subtypes SSTR2a, SSTR3 and SSTR5 in peripheral blood of neuroendocrine lung cancer affected patients.
Cell Oncol (Dordr). 2011; 34(5):435-41 [PubMed] Related Publications
BACKGROUND: Somatostatin (SS) acts as a universal endocrine off-switch, and also inhibits the growth of neuroendocrine tumours through its specific receptors (SSTRs). Somatostatin receptors are G-protein-coupled receptors, which are encoded by five separate genes (SSTR1-5). Short peptide analogues demonstrate specific binding only for the subgroup consisting of SSTR2a, SSTR3 and SSTR5. Moreover, previous studies reported that expression of mRNA for SSTR2a correlated with therapeutic outcome in patients with carcinoid tumours treated with somatostatin analogs.
PURPOSE: To develop and apply a Real Time Quantitative PCR technique (RT-qPCR) to compare and contrast the mRNA levels of SSTR2a, SSTR3 and SSTR5 in Neuroendocrine Lung Cancer affected patients.
METHODS: Peripheral blood samples from 21 neuroendocrine lung cancer affected patients (14 SCLC, 6 LC and 1 LCNEC) subjected to scintigraphy with (111)In-DTPA-D-Phe(1)-octreotide (OctreoScan) and 24 healthy blood donors were investigated by RT-qPCR. mRNA levels for SSTR2a, SSTR3 and SSTR5 were measured in peripheral blood samples with a relative quantification method using plasmid dilutions as calibration curves and GAPDH as reference gene.
RESULTS: A statistically significant increase in target genes/GAPDH copy number ratio was found for SSTR2a (median 38; IQR 22-141) and SSTR5 (median 51; IQR 19-499) in neuroendocrine lung cancer affected patients as compared with samples from healthy blood donors (P ≤ 0.0003 and P ≤ 0.0005). Since low levels of expression were detected in the control group for all three genes, optimal cut-off values were assessed using ROC curve analyses and were equal to 9.05 for SSTR2a and 16.97 for SSTR5. These cut off values resulted in a sensitivity of 86% (95%IC 65-95) for both markers and a specificity of 83% (95%IC 64-93%) and 79% (95%IC 60-91%) for SSTR2a and SSTR5 respectively. Comparison between OctreoScan results and RT-qPCR analysis demonstrated agreement in 76% of the cases.
CONCLUSIONS: Our results suggest that SSTR2a and SSTR5 mRNAs are detectable in peripheral blood of neuroendocrine lung cancer affected patients using real-time quantitative PCR, with a good agreement with OctreoScan. The high sensitivity of this non-invasive molecular technique suggests that this method could represent a useful tool in the clinical management of neuroendocrine lung cancers.

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