Gene Summary

Gene:SST; somatostatin
Aliases: SMST
Summary:The hormone somatostatin has active 14 aa and 28 aa forms that are produced by alternate cleavage of the single preproprotein encoded by this gene. Somatostatin is expressed throughout the body and inhibits the release of numerous secondary hormones by binding to high-affinity G-protein-coupled somatostatin receptors. This hormone is an important regulator of the endocrine system through its interactions with pituitary growth hormone, thyroid stimulating hormone, and most hormones of the gastrointestinal tract. Somatostatin also affects rates of neurotransmission in the central nervous system and proliferation of both normal and tumorigenic cells. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (18)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Prostate Cancer
  • Cell Proliferation
  • Protein Precursors
  • In Situ Hybridization
  • Immunohistochemistry
  • Amino Acid Sequence
  • Gene Expression
  • Base Sequence
  • Brain Tumours
  • Neuroendocrine Tumors
  • Cell Line
  • Substance P
  • Adenocarcinoma
  • Somatostatinoma
  • Antineoplastic Agents, Hormonal
  • Gene Expression Profiling
  • Virus Replication
  • Chromosome 3
  • Thymidine
  • Stomach Cancer
  • Oligonucleotide Array Sequence Analysis
  • Brain Tumours
  • Neuropeptides
  • Nucleic Acid Hybridization
  • Cervical Cancer
  • DNA
  • DNA Methylation
  • Octreotide
  • Carcinoma, Medullary
  • Teratocarcinoma
  • Gastrointestinal Cancers
  • Molecular Sequence Data
  • Thyrotropin
  • Promoter Regions
  • Biomarkers, Tumor
  • Receptors, Somatostatin
  • Messenger RNA
  • Pituitary Tumors
  • Somatostatin
  • Transcription
  • Pancreatic Cancer
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SST (cancer-related)

Misawa K, Mima M, Imai A, et al.
The neuropeptide genes
Clin Epigenetics. 2018; 10:52 [PubMed] Free Access to Full Article Related Publications
Background: Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Identifying biomarkers for HNSCC that will progress and cause death is a critical research area, particularly if the biomarker can be linked to selection of patients. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of five neuropeptide gene promoters. The promoter methylation status was determined by quantitative methylation-specific PCR in 230 cases of HNSCC; 58 hypopharynx, 45 larynx, 56 oropharynx, and 71 oral cavity tumor samples were studied.
Results: The somatostatin (
Conclusion: In this study, we demonstrated the methylation status of the neuropeptide-encoding genes

Fortunati N, Guaraldi F, Zunino V, et al.
Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells.
Environ Res. 2017; 158:660-668 [PubMed] Related Publications
An increased rate of acromegaly was reported in industrialized areas, suggesting an involvement of environmental pollutants in the pathogenesis and behavior of GH-secreting pituitary adenomas. Based on these premises, the aim of the study was to evaluate the effects of some widely diffused pollutants (i.e. benzene, BZ; bis(2-ethylhexyl) phthalate, DEHP and polychlorinated biphenyls, PCB) on growth hormone secretion, the somatostatin and estrogenic pathways, viability and proliferation of rat GH-producing pituitary adenoma (GH3) cells. All the pollutants induced a statistically significant increase in GH secretion and interfered with cell signaling. They all modulated the expression of SSTR2 and ZAC1, involved in the somatostatin signaling, and the expression of the transcription factor FOXA1, involved in the estrogen receptor signaling. Moreover, all the pollutants increased the expression of the CYP1A1, suggesting AHR pathway activation. None of the pollutants impacted on cell proliferation or viability. Present data demonstrate that exposure to different pollutants, used at in vivo relevant concentrations, plays an important role in the behavior of GH3 pituitary adenoma cells, by increasing GH secretion and modulating several cellular signaling pathways. These observations support a possible influence of different pollutants in vivo on the GH-adenoma aggressiveness and biological behavior.

Yu B, Zhang Z, Song H, et al.
Clinical Importance of Somatostatin Receptor 2 (SSTR2) and Somatostatin Receptor 5 (SSTR5) Expression in Thyrotropin-Producing Pituitary Adenoma (TSHoma).
Med Sci Monit. 2017; 23:1947-1955 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism. Somatostatin analogs have proved to be effective for inhibiting pituitary hormones secretion, working via interactions with somatostatin receptors (SSTRs). Moreover, antiproliferative activity of somatostatin analog is now demonstrated in several studies. In the present study, we determined the relative predominance of SSTR2 and SSTR5 subtypes among the different types of adenomas, especially TSHoma, and investigated the relationship between efficacy of short-term octreotide (OCT) treatment and SSTR expression. MATERIAL AND METHODS Serum hormone determinations and histological findings in resected tissue resulted in 5 diagnoses: 16 TSHomas, 8 acromegaly, 3 prolactinomas, 3 corticotropinomas, 4 clinically nonfunctioning adenomas (NFPAs), and 4 normal pituitary specimens. IHC was performed on formalin-fixed and paraffin-embedded tissue in tissue microarrays. RESULTS IHC of SSTR subtypes in the different cohorts showed SSTR2 staining intensity scores higher than SSTR5 in TSHoma, acromegaly and prolactinoma, whereas the expression of SSTR5 was stronger than SSTR2 in corticotropinoma and NFPA. SSTR2 and SSTR5 expressions were significantly higher in TSHoma than in other pituitary adenomas. OCT treatment for a median of 8.4 days (range: 3-18 days) and with a total median dose of 1.9 mg (range: 0.9-4.2 mg) showed a significant decrease of thyroid hormone levels (TSH [μIU/ml] in all patients. Patients with low SSTR5 expression presented a significantly higher TSH suppression rate (P values <0.05). CONCLUSIONS The present data confirm that somatostatin analogs should be considered as a medical alternative to surgical treatment, especially in patients with TSHoma, and short-term response to OCT therapy may be related to the expression of SSTR5.

Verlaat W, Snijders PJF, Novianti PW, et al.
Genome-wide DNA Methylation Profiling Reveals Methylation Markers Associated with 3q Gain for Detection of Cervical Precancer and Cancer.
Clin Cancer Res. 2017; 23(14):3813-3822 [PubMed] Related Publications

Luque RM, Villa-Osaba A, L-López F, et al.
Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode.
Breast Cancer Res. 2016; 18(1):29 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown.
METHODS: The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland.
RESULTS: Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity.
CONCLUSIONS: Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer.

Sundaresan S, Kang AJ, Hayes MM, et al.
Deletion of
Gut. 2017; 66(6):1012-1021 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal.
OBJECTIVE: To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines.
DESIGN: The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27
RESULTS: The combination of conditional Men1 deletion in the absence of somatostatin led to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27
CONCLUSIONS: Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27

Xie YM, Li X, Yan LN, et al.
[The Expressions of Somatostatin and Cycloxygenase-2 in Chronic Hepatitis, Hepatic Cirrhosis, Precancerous Lesion and Hepatocellular Carcinoma].
Sichuan Da Xue Xue Bao Yi Xue Ban. 2015; 46(5):710-6 [PubMed] Related Publications
OBJECTIVE: To investigate the expression difference of somatostatin (SST) , SST receptors (SSTR) and COX-2 in chronic hepatitis, hepatic cirrhosis, precancerous lesion and hepatocellular Carcinoma, and explore the relationship between portal hypertension and SST/SSTR expressions.
METHODS: A series of human liver tissues were obtained from surgery, including normal liver 4 cases, chronic hepatitis 14 cases, hepatic cirrhosis 40 cases, precancerous lesion 40 cases and HCC tissues 40 cases. Peripheral bloods were collected from 20 patients before and after the operation of transjugular intrahepatic portosystemic shunt (TIPS). SSTR 1-5 subtypes in hepatic tissues were detected by immunohistochemical study and RT-PCR. Levels of SST and COX-2 were quantified by radioimmunoassay and Western blot.
RESULTS: 90% of precancerosis expressed high levels of SSTR 2, 5 subtypes, and SSTR mainly distributed surrounding portal vein. At lest 60%o of HCC expressed SSTR 2, 5 subtypes, and there were positive correlations between levels of SSTR 1-5 and SST. Levels of SST in peripheral blood of cirrhotic patients significantly increased after TIPS(P<0. 05). Levels of COX-2 were highest in cirrhosis (about 90%), and decreased in precancerosis (about 80%) and HCC tissues.
CONCLUSIONS: Precancerosis or early stage of HCC may be the optimum time for synergetic medication of SST analogue and COX-2 inhibitor.

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.

Leiszter K, Sipos F, Galamb O, et al.
Promoter hypermethylation-related reduced somatostatin production promotes uncontrolled cell proliferation in colorectal cancer.
PLoS One. 2015; 10(2):e0118332 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line.
METHODS: Colonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion.
RESULTS: In case of normal aging SST mRNA expression did not alter, but decreased in cancer (p < 0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70% ± 0.79%) compared to CRC (0% ± 0%) (p < 0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2% ± 11.6%) compared to healthy young individuals (3.5% ± 1.9%) (p < 0.05).
CONCLUSIONS: In cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation.

Alonso-Gordoa T, Capdevila J, Grande E
GEP-NETs update: Biotherapy for neuroendocrine tumours.
Eur J Endocrinol. 2015; 172(1):R31-46 [PubMed] Related Publications
Neuroendocrine tumours (NETs) represent a less frequent and heterogeneous group of tumours, which has experienced, in recent years, a significant increase in effective therapeutic possibilities overcoming the disappointing results from chemotherapy. Initial improvements in treatment strategies came from somatostatin analogues (SSAs) that have widely demonstrated a significant improvement in symptomatic relief and tumour control growth by a complex mechanism of action over cell survival, angiogenesis and immunomodulation. Recent investigations have pointed out novel SSAs with a wider binding profile (pasireotide), chimeric molecules against somatostatin receptors and dopamine receptors and the combination with targeted agents, such as mTOR inhibitors or antiangiogenic agents. Immunotherapy is the second cornerstone in NET treatment and has been represented with interferon alpha for a long time, with a demonstrated activity on tumour and clinical response. Its less manageable adverse events have limited its usage. However, different checkpoints in immune system regulation have been effectively targeted in different solid tumours, and novel approaches are currently arising in NETs. In conclusion, biotherapy remains an active treatment strategy for initial approach in patients with NETs. Further investigation on patients' selection, molecular profiles, treatment sequence or combination and optimisation of current and novel biotherapy agents is required.

Kozłowska A, Majewski M, Jana B
Changes in the cholinergic innervation pattern of porcine ovaries with cysts induced by dexamethasone administration.
J Mol Neurosci. 2014; 54(1):10-9 [PubMed] Free Access to Full Article Related Publications
We revealed earlier that induction of ovarian cysts in gilts by dexamethasone phosphate disodium salt (DXM) administration from the follicular phase of the estrous cycle (EC) changed the cholinergic innervation of the gonad. In the present study, the innervation of porcine ovaries by vesicular acetylcholine transporter (VAChT)-, neuronal nitric oxide synthase (nNOS)-, vasoactive intestinal peptide (VIP)- and somatostatin (SOM)-immunoreactive (IR) fibres, after induction of cystic changes from the middle luteal phase of the EC, was determined. The cystic changes were induced by DXM injections from days 7 to 21 of the EC, and 11 days later, the ovaries were collected. In the cystic ovaries, VAChT-, nNOS- and SOM-IR fibres were found around cysts and small tertiary follicles; nNOS-IR and also VAChT-IR fibres were observed near secondary follicles and veins; and VAChT- and nNOS-IR fibres were not found around cortical arteries. The number of VIP-IR fibres increased near the cysts and within the ground plexus, while the number of VAChT-IR fibres decreased within the medullar part of this structure. Thus, our study showed changes in the cholinergic innervation pattern of the porcine cystic ovaries induced from the middle phase of the cycle and confirmed that cystic ovary innervation depends partly on the phase of the EC in which the induction of cysts was started.

Tulassay Z
[Editor's commentary: Clinical use of somatostatin].
Orv Hetil. 2013; 154(39):1526 [PubMed] Related Publications

Lécolle K, Bégard S, Caillierez R, et al.
Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors.
Gene Ther. 2013; 20(3):283-97 [PubMed] Related Publications
Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood-brain barrier, which restricts the penetration of most drugs into the central nervous system. Locoregional treatment strategies thus become mandatory. In this context, viral tools are of great interest for the selective delivery of genes into tumoral cells. Gliomas express high levels of type 2 somatostatin receptors (sstr2A), pinpointing them as suitable targets for the improvement of transduction efficiency in these tumors. We designed a new adenoviral vector based on the introduction of the full-length somatostatin (SRIF (somatotropin release-inhibiting factor)) sequence into the HI loop of the HAdV fiber protein. We demonstrate that (i) HAdV-5-SRIF uptake into cells is mediated by sstr2A, (ii) our vector drives high levels of gene expression in cells expressing endogenous sstr2A, with up to 65-fold enhancement and (iii) low doses of HAdV-5-SRIF are sufficient to infect high-grade human primary glioblastoma cells. Adenoviral vectors targeting SRIF receptors might thus represent a promising therapeutic approach to brain tumors.

Lyons J, Anthony CT, Woltering EA
The role of angiogenesis in neuroendocrine tumors.
Endocrinol Metab Clin North Am. 2010; 39(4):839-52 [PubMed] Related Publications
The first studies to assess in vitro angiogenesis in neuroendocrine tumors used animal-based assays to study the antiangiogenic properties of somatostatin analogs. Current technologies enable investigators to directly appraise the in vitro angiogenic response of an individual's neuroendocrine tumor with and without potential antiangiogenic reagents. This article describes the evolution of methods to assess in vitro angiogenesis in neuroendocrine tumors and describes some of the clinical data.

Jackson K, Soutto M, Peng D, et al.
Epigenetic silencing of somatostatin in gastric cancer.
Dig Dis Sci. 2011; 56(1):125-30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, has potent antitumor and anti-secretory activity in several human cancers.
AIMS: This study was performed to investigate the SST gene expression levels and possible epigenetic mechanisms that regulate expression of SST in gastric adenocarcinomas.
METHODS: Quantitative real-time (RT)-PCR and quantitative bisulfite pyrosequencing were used to study primary gastric cancer tissue samples and cell lines.
RESULTS: Quantitative RT-PCR analysis revealed down-regulation of the SST transcript in 93% of gastric carcinoma samples (30/32), compared with 21 normal samples (P<0.001). Because of the presence of a large CpG island in the SST promoter, we next examined its promoter DNA methylation levels by use of quantitative bisulfite pyrosequencing. The results revealed a significant increase in SST promoter DNA methylation in tumor samples compared with normal samples (P<0.05). Promoter DNA hypermethylation and silencing of SST was also detected in seven gastric cancer cell lines that we tested. To confirm the role of promoter DNA methylation as an epigenetic mechanism regulating SST expression, AGS gastric cancer cells were treated with 5-Aza-dc. This treatment led to reduction of promoter DNA methylation levels of SST accompanied by restoration of its mRNA expression.
CONCLUSIONS: Our results indicate that promoter DNA methylation levels play a critical role in regulating SST expression in gastric cancer. This finding provides a foundation for further studies on the role of SST in gastric carcinogenesis and its potential as a biomarker for gastric cancers.

Strosberg J, Kvols L
Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors.
World J Gastroenterol. 2010; 16(24):2963-70 [PubMed] Free Access to Full Article Related Publications
Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors. A phase III, randomized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to significantly lengthening time to tumor progression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.

Zhang X, Yang JJ, Kim YS, et al.
An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer.
Int J Oncol. 2010; 36(2):405-14 [PubMed] Related Publications
We have identified an 8-gene signature with significant expression differences between gastric cancer and normal gastric tissues. This 8-gene set can predict the normal and cancer status of gastric tissues with more than 96% accuracy in a totally independent microarray dataset. The 8 genes are composed of down-regulated KLF4, GPX3, SST and LIPF, together with up-regulated SERPINH1, THY1 and INHBA in gastric cancer. To corroborate the differential gene expression pattern, we chose GPX3 and examined its expression pattern in detail. A comparison of GPX3 expression pattern shows a broader down-regulated pattern in multiple types of cancers, including cervical, thyroid, head and neck, lung cancers and melanoma than in healthy controls. An immuno-histostaining analysis in tissue microarrays confirms GPX3 down-regulation in gastric cancer. Mechanism-wise GPX3 down-regulation in gastric cancer is due to promoter hypermethylation. Collectively, these results show a correct identification of 8 genes as gastric cancer biomarkers.

Kang JU, Koo SH, Kwon KC, et al.
Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.
BMC Cancer. 2009; 9:237 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The underlying genetic alterations for squamous cell carcinoma (SCC) and adenocarcinoma (AC) carcinogenesis are largely unknown.
METHODS: High-resolution array- CGH was performed to identify the differences in the patterns of genomic imbalances between SCC and AC of non-small cell lung cancer (NSCLC).
RESULTS: On a genome-wide profile, SCCs showed higher frequency of gains than ACs (p = 0.067). More specifically, statistically significant differences were observed across the histologic subtypes for gains at 2q14.2, 3q26.2-q29, 12p13.2-p13.33, and 19p13.3, as well as losses at 3p26.2-p26.3, 16p13.11, and 17p11.2 in SCC, and gains at 7q22.1 and losses at 15q22.2-q25.2 occurred in AC (P < 0.05). The most striking difference between SCC and AC was gains at the 3q26.2-q29, occurring in 86% (19/22) of SCCs, but in only 21% (3/14) of ACs. Many significant genes at the 3q26.2-q29 regions previously linked to a specific histology, such as EVI1,MDS1, PIK3CA and TP73L, were observed in SCC (P < 0.05). In addition, we identified the following possible target genes (> 30% of patients) at 3q26.2-q29: LOC389174 (3q26.2),KCNMB3 (3q26.32),EPHB3 (3q27.1), MASP1 and SST (3q27.3), LPP and FGF12 (3q28), and OPA1,KIAA022,LOC220729, LOC440996,LOC440997, and LOC440998 (3q29), all of which were significantly targeted in SCC (P < 0.05). Among these same genes, high-level amplifications were detected for the gene, EPHB3, at 3q27.1, and MASP1 and SST, at 3q27.3 (18, 18, and 14%, respectively). Quantitative real time PCR demonstrated array CGH detected potential candidate genes that were over expressed in SCCs.
CONCLUSION: Using whole-genome array CGH, we have successfully identified significant differences and unique information of chromosomal signatures prevalent between the SCC and AC subtypes of NSCLC. The newly identified candidate target genes may prove to be highly attractive candidate molecular markers for the classification of NSCLC histologic subtypes, and could potentially contribute to the pathogenesis of the squamous cell carcinoma of the lung.

Johansson M, McKay JD, Wiklund F, et al.
Genetic variation in the SST gene and its receptors in relation to circulating levels of insulin-like growth factor-I, IGFBP3, and prostate cancer risk.
Cancer Epidemiol Biomarkers Prev. 2009; 18(5):1644-50 [PubMed] Related Publications
BACKGROUND: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels.
MATERIALS AND METHODS: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC).
RESULTS: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels.
CONCLUSIONS: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk.

Pasquali D, Rossi V, Conzo G, et al.
Effects of somatostatin analog SOM230 on cell proliferation, apoptosis, and catecholamine levels in cultured pheochromocytoma cells.
J Mol Endocrinol. 2008; 40(6):263-71 [PubMed] Related Publications
Surgery is the primary therapy for pheochromocytoma (PHEO), a catecholamine-producing tumor. Benign and malignant PHEO could develop recurrences, and the intraoperative risk of recurrent PHEO is an important unresolved issue. Non-surgical treatments of PHEO recurrence would therefore better prepare patients for reintervention as well as provide them with palliative management. We investigated the effects of the new somatostatin analog (pasireotide) SOM230 versus octreotide (OCT) in primary PHEO cell cultures (Pheo-c). Pheo-c from six benign surgical samples were set up and characterized by immunocytochemistry. Real-time PCR, using both PHEO tissues and Pheo-c, showed different levels of somatostatin receptor(1-5) mRNA expression. Cells treated with various doses of OCT or SOM230 for 48 and 72 h were analyzed to assess their effects on cell proliferation and apoptosis and catecholamine levels. Even if reduction of cell viability was observed in Pheo-c treated for 48 h with either OCT or SOM230 and this effect increased after 72 h, a more significant inhibition of cell growth as well as a significantly higher induction of apoptosis was seen in Pheo-c treated with SOM230 versus OCT. In particular, apoptosis in Pheo-c was detected after 48 h and was associated with increased expression and activation of caspase-3 and cleaved poly(ADP-ribose) polymerase. OCT 10(-6) M and SOM230 10(-7) M significantly reduced catecholamine levels. Our results indicate that while both OCT and SOM230 modulate cell growth and apoptosis and catecholamine levels in Pheo-c through specific receptors, SOM230 is more effective. This improves our knowledge on the mechanism of SOM230 action in PHEO and supports a possible therapeutic use in benign PHEO recurrence.

Jin Z, Mori Y, Hamilton JP, et al.
Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis.
Cancer. 2008; 112(1):43-9 [PubMed] Related Publications
BACKGROUND: The promoter of somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, is hypermethylated in 80% of human colon cancers. The aim of the current study was to investigate whether and at what stage promoter hypermethylation of SST is involved in human esophageal carcinogenesis.
METHODS: SST promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction (PCR) (MSP) in 260 human esophageal tissue specimens. Real-time reverse-transcriptase PCR and MSP were also performed on esophageal cancer cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC).
RESULTS: SST hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) from normal esophagus (NE) (P < .01). Both SST methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett metaplasia without dysplasia or EAC (BE), low-grade and high-grade (HGD) dysplasia occurring in BE, EAC, and ESCC than in NE (P < .01). SST hypermethylation frequency was significantly lower in NE (9%) than in BE (70%), HGD (71.4%), or EAC (71.6%), whereas 14 (53.8%) of 26 ESCCs exhibited SST hypermethylation. There was a significant relation between SST hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Demethylation of KYSE220 ESCC and OE33 EAC cells with 5-Aza-dC reduced SST methylation and increased SST mRNA expression. SST mRNA levels in native unmethylated EACs were significantly higher than in native methylated EACs (P < .05).
CONCLUSIONS: SST promoter hypermethylation is a common event in human esophageal carcinomas and is related to early neoplastic progression in Barrett esophagus.

Resmini E, Dadati P, Ravetti JL, et al.
Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient.
J Clin Endocrinol Metab. 2007; 92(5):1592-9 [PubMed] Related Publications
CONTEXT: Criteria to define the response to somatostatin (SS) analogs (SSA) in acromegaly are based on biochemical control of the disease. However, the mechanisms of action of SSAs in inhibiting tumor growth and hormonal secretion are only partially understood, and the two effects may occur independently.
OBJECTIVE: The objective of the study was to investigate the dissociation between antiproliferative and antisecretive effects of SSA in an octreotide-resistant patient displaying dramatic tumor shrinkage during primary therapy with octreotide LAR.
DESIGN AND SETTING: We characterized somatostatin and dopamine D(2) receptor expression by immunohistochemistry and real-time RT-PCR. The effects of different receptor-selective, bispecific analogs, and chimeric somatostatin/dopamine compounds on GH secretion and cell proliferation in primary cell cultures of the tumor were assessed.
RESULTS: The expression of SS receptor subtypes (sst)(5) and D(2) receptor was higher, compared with the other receptor subtypes. GH inhibition by SS-14 and the two chimeric somatostatin/dopamine compounds was scant but greater than subtype-selective and sst(2)/sst(5) bispecific agonists. Conversely, cell growth was potently inhibited by all test substances. However, SS-14, sst(2)/sst(5) bispecific agonist, and chimeric molecules were more potent than the other compounds.
CONCLUSIONS: The significant antiproliferative effect of octreotide seems to be related to the higher expression of sst(5) and the negligible antihormonal effect to the lower expression of sst(2). However, activation of multiple receptors by new analogs may produce better control of tumor cell activities. The dissociation between antisecretive and antiproliferative effects observed in vivo and in vitro confirms that SSAs may induce tumor shrinkage despite the lack of effect on GH secretion.

Judd LM, Bredin K, Kalantzis A, et al.
STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis.
Gastroenterology. 2006; 131(4):1073-85 [PubMed] Related Publications
BACKGROUND & AIMS: The gp130(757F/F) mouse is a well-characterized and robust model of distal gastric tumorigenesis displaying many of the characteristics of human intestinal type gastric cancer. Key to the development of tumors in this model, and in many examples of human tumor development, is hyperactivation of the transcription factor STAT3. This study addressed the requirement for STAT3 activation in tumor initiation and characterized some of the genes downstream of STAT3 required for tumor development. Furthermore, the interaction among STAT3, the microbial environment, and tumorigenesis was evaluated.
METHODS: The role of STAT3 in gastric tumor development was assessed in detail in gp130(757F/Y757F):STAT3(+/-) mice displaying reduced STAT3 activity. Tumor size was quantified morphologically, and the effects on endocrine cell populations, neovascularization, and inflammatory cell infiltration as well as the outcome of STAT3 activation on transcription of a number of genes relevant in growth and inflammation were quantified.
RESULTS: Loss of one STAT3 allele in gp130(757F/F) mice reduced the frequency and rate of tumor development because of inhibition of proliferation-induced glandular hyperplasia. There was also a concomitant reduction in the degree of inflammatory infiltration and cytokine and chemokine expression, angiogenesis, and expression of metalloproteinases and growth factors. Antimicrobial treatment of gp130(757F/F) mice slowed tumor growth coincident with reduced macrophage and neutrophil infiltration.
CONCLUSIONS: Activation of STAT3 and the microbial environment are pivotal for gastric tumor initiation and development in the gp130(757F/F) mouse, thus supporting the notion that STAT3 activation may play a role in human gastric cancer development.

Mori Y, Cai K, Cheng Y, et al.
A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer.
Gastroenterology. 2006; 131(3):797-808 [PubMed] Related Publications
BACKGROUND & AIMS: Gene silencing via promoter hypermethylation is a central event in the pathogenesis of cancers. To identify novel methylation targets in colon cancer, we conducted a genome-wide, microarray-based, in silico, and epigenetic search.
METHODS: Complementary DNA microarray experiments were first performed to identify genes down-regulated in primary colon cancers and up-regulated in colon cancer cell lines after global DNA demethylation by 5-aza-2'-deoxycitidine. Candidate methylation targets were then identified by combining these microarray data with in silico genetic and functional searches. Candidate genes recognized by these searches were further investigated for promoter hypermethylation in colon cancer using methylation-specific polymerase chain reaction.
RESULTS: We identified 51 novel and 3 known candidate methylation targets. Subsequent epigenetic analysis revealed that primary colon cancers demonstrated frequent methylation of somatostatin (SST, 30 of 34 cases, 88%) and the substance P precursor gene tachykinin-1 (TAC1; 16 of 34 cases, 47%). TAC1 methylation intensity was significantly higher in Dukes A/B than in Dukes C/D cancers (P = .01). SST methylation intensity was significantly higher in low-level microsatellite instability (MSI-L) than in non-MSI-L cancers (P = .02). Methylation was associated with messenger RNA down-regulation for both SST and TAC1. Furthermore, we isolated 5 additional novel promoter methylation targets: NELL1, AKAP12, caveolin-1, endoglin, and MAL.
CONCLUSIONS: These data strongly suggest that SST and TAC1 are involved in colon carcinogenesis. Further studies are now indicated to elucidate mechanisms underlying their involvement in colon cancer and their values as clinical biomarkers. NELL1, AKAP12, caveolin-1, endoglin, and MAL are also promising tumor suppressor gene candidates deserving of further study.

Engel JB, Schally AV, Halmos G, et al.
Targeted therapy with a cytotoxic somatostatin analog, AN-238, inhibits growth of human experimental endometrial carcinomas expressing multidrug resistance protein MDR-1.
Cancer. 2005; 104(6):1312-21 [PubMed] Related Publications
BACKGROUND: Chemoresistance mediated by membrane transporters such as multidrug resistance (MDR-1) glycoprotein remains a challenge in the chemotherapy treatment of advanced or recurrent endometrial carcinoma. Targeted chemotherapy might overcome this resistance. The cytotoxic somatostatin (SST) analog, AN-238, consists of a superactive derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), linked to the SST analog carrier, RC-121. This conjugate binds strongly to SST receptor subtypes (sst) 2a (sst2(a)) and 5 (sst(5)) and can be targeted to tumors that express these receptors.
METHODS: The presence of sst2(a) and sst(5) was determined in 3 human endometrial carcinoma cell lines (HEC-1A, RL-95-2, and AN3CA). Nude mice bearing xenografts of these cancers were treated with AN-238 and its radical, AN-201. The antitumor effects and toxicity were compared. The authors studied the effects of AN-238 and AN-201 on the expression levels of MDR-1, multidrug resistance related protein (MRP-1), and breast carcinoma resistance protein (BCRP) by real-time polymerase chain reaction.
RESULTS: The authors demonstrated the presence of mRNA and receptor protein for sst(2a) and sst(5) on HEC-1A, RL-95-2, and AN3CA tumors. AN-238 significantly (P < 0.05) inhibited the growth of these tumors, whereas AN-201 had no effect. Blockade of SST receptors nullified the effects of AN-238. In all 3 endometrial carcinoma lines, AN-238 caused a weaker induction of MDR-1 than AN-201. No major induction of MRP-1 and BCRP occurred after treatment with AN-238 or AN-201.
CONCLUSIONS: Targeted chemotherapy with the cytotoxic SST analog, AN-238, inhibited powerfully the growth of endometrial carcinoma, which express SST receptors, regardless of their expression level of MDR-1.

Lasfer M, Vadrot N, Schally AV, et al.
Potent induction of apoptosis in human hepatoma cell lines by targeted cytotoxic somatostatin analogue AN-238.
J Hepatol. 2005; 42(2):230-7 [PubMed] Related Publications
BACKGROUND/AIMS: The efficacy of a targeted cytotoxic hybrid somatostatin analogue AN-238 and of its superactive radical 2-pyrrolinodoxorubicin (AN-201) to induce apoptosis of HepG2 and Hep3B human hepatoma cell lines were studied. AN-238 was designed to selectively target tumor cells expressing somatostatin receptor subtypes (sst(s)). Its effects on HepG2 or Hep3B cells displaying or lacking tumor suppressor p53, respectively, were compared. Normal rat isolated hepatocytes were also tested.
METHODS: sst(s) were characterized by binding assays and RT-PCR. Cytotoxicity was quantified by flow cytometry. DNA fragmentation was studied by gel electrophoresis, PARP cleavage by Western blot and ROS formation using fluorescent probes.
RESULTS: Specific binding of iodinated RC-160 to HepG2 and Hep3B cells, and its displacement by AN-238 was characterized. mRNA for hsst(2A) was found in both cell lines. Flow cytometry showed a stronger effect of AN-238 than AN-201 to induce sub-G1 phase. DNA fragmentation, nuclear bodies, and PARP cleavage were observed. In addition, AN-238 increased formation of ROS more potently than AN-201. However, no inductions of DNA fragmentation by AN-201 or AN-238 were observed on rat hepatocytes.
CONCLUSIONS: Our results indicate that, in liver cancer, the cytotoxic somatostatin analogue AN-238 is a powerful agent that can induce apoptosis, through sst(s) and independently of p53.

Modlin IM, Kidd M, Hinoue T, et al.
Molecular strategies and 111in-labelled somatostatin analogues in defining the management of neuroendocrine tumour disease: a new paradigm for surgical management.
Surgeon. 2003; 1(3):137-43 [PubMed] Related Publications
This manuscript provides a gene-chip examination of gastric ECL cell proliferation in an animal model of neuroendocrine tumour disease. Data that were used to identify molecular targets were then utilised to develop novel therapeutic strategies as appropriate adjuncts to surgery in human disease. Alterations in growth-mediated cell signaling (the AP-1 pathway) and in the cell cycle were identified in ECL cell tumours in the animal model and confirmed in human tumour tissue. The growth-inhibitory somatostatin receptor subtype 2 was identified as a potential clinical target. An investigation of patients with neuroendocrine tumours treated using SSTR2 targeted radiotherapy [111In]pentetreotide producing encouraging preliminary results. Fifty-six per cent of patients with evaluable hormone markers demonstrated stable levels or a significant decrease in one or more measured markers. This data demonstrate that gene pathways recognised to be altered in an animal model of a human disease can be used to identify therapeutic agents. This approach was successfully used to discover novel strategies that can be both effective and appropriate adjuncts to surgery for patients with neuroendocrine tumour disease.

Davies JS, Holter JL, Knight D, et al.
Manipulating sorting signals to generate co-expression of somatostatin and eGFP in the regulated secretory pathway from a monocistronic construct.
J Mol Endocrinol. 2004; 33(2):523-32 [PubMed] Related Publications
Targeted overexpression of biologically active peptides represents a powerful approach to the functional dissection of neuroendocrine systems. However, the requirement to generate separate, biologically active and reporter molecules necessitates the use of internal ribosome entry site (IRES) technology, which often results in preferential translation of the second cistron. We report here a novel approach in which the proteolytic processing machinery of the regulated secretory pathway (RSP) has been exploited to generate multiple mature proteins from a monocistronic construct that encodes a single precursor. This was achieved by duplication of the pre-pro cleavage sites in pre-prosomatostatin cDNA. The duplicated site included 10 flanking amino acids on either side of the Gly-Ala cleavage position. This enabled the incorporation of a foreign protein-coding sequence (in this case, enhanced green fluorescent protein (eGFP)) between these sites. The pre-eGFP-prosomatostatin (PEPS) construct generated co-localized expression of fully processed eGFP and somatostatin to the RSP of transiently transfected AtT20 cells. This approach represents an advance upon bicistronic and other extant approaches to the targeting of multiple, biologically active proteins to neuroendocrine systems, and, importantly, permits the co-expression of fluorescent markers with biologically active neuropeptides. In this study, our demonstration of the fusion of the first 10 amino acids of the prosomatostatin sequence to the N-terminus of eGFP shows that this putative sorting sequence is sufficient to direct expression to the RSP.

Sinisi AA, Rossi V, Prezioso D, et al.
The role of somatostatin analogs in the management of prostate cancer.
J Endocrinol Invest. 2003; 26(8 Suppl):120-4 [PubMed] Related Publications

O'Driscoll L, Gammell P, Clynes M
Expression in murine teratocarcinoma F9 cells of transcription factors involved in pancreas development.
Transplant Proc. 2004; 36(4):1151-8 [PubMed] Related Publications
BACKGROUND: Although it has been established that formation and functional differentiation of the pancreas from embryonic endoderm is associated with activation/inactivation of many genes controlled by specific sets of transcription factors, the role and activation sequence of individual transcription factors has not yet been fully elucidated. This study sought to differentiate a murine teratocarcinoma cell line, F9, to endodermal-like cells and, subsequently; to investigate the effects of regulated expression of transcription factors in pancreas development.
METHODS: Following differentiation using retinoic acid and db cAMP (RAC), resulting F9 cells (F9-RAC) were transfected with cDNAs for PDX-1, ngn3, beta 2/NeuroD (beta 2), and Nkx2.2, singly or in combination. Expression of these transcription factors was investigated using RT-PCR and immunofluorescence techniques. RT-PCR analysis was used to assess the subsequent effects of expression of these factors on endogenous genes related to pancreas development.
RESULTS: Regulated differentiation of F9 cells generated endodermal-like cell types. Following transfection, PDX-1, ngn3, beta 2, and Nkx2.2 were expressed in F9-RAC cells, with their proteins localized mainly in cellular nuclei. Expression of these factors apparently did not affect the endogenous expression of preproinsulin, PDX-1, beta 2, Isl1, Pax4, Pax6, Sonic hedgehog, and Indian hedgehog.
CONCLUSION: This study describes the successful transient expression of transcription factors related to pancreas development, following directed differentiation of F9 cells to endoderm-like cells, and shows that treatment of F9 cells with a combination of RAC causes up-regulation of genes relevant to pancreatic development. The lack of further effect of regulated transcription factor expression on these genes may suggest that parietal endoderm- like cells derived from F9 cells is not the optimal lineage from which to develop beta cells. It may be useful to include F9-derived visceral endoderm in future studies.

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