Progression To Esophageal Adenocarcinoma Research Articles

Pathogenesis and progression of oesophageal adenocarcinoma varies by prior diagnosis of Barrett's oesophagus.

Background:The absolute risk of oesophageal adenocarcinoma (EA) among individuals with Barrett's oesophagus (BE) is low and a majority of EA cases are diagnosed among individuals with no prior BE diagnosis. To ensure that insights from EA case–control studies are transferable to clinical management of BE populations, we conducted a case–case study to compare the clinical presentation, medical history and survival of EA cases with and without a prior BE diagnosis in the Surveillance, Epidemiology and End Results Medicare database.Methods:Eligible EA cases were diagnosed at age ⩾68 years during 1994–2009. There were 5271 EA cases in this study, 87% of which did not have a prior diagnosis of BE (EA-no prior BE).Results:Multivariable case–case comparisons evidenced adverse associations of GERD, ever cigarette smoking, hypertension, dyslipidemia, weight loss, peptic ulcer and irritable bowel disease each in EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose and diabetes did not differ between groups. EA-prior BE cases were diagnosed with less advanced disease, were more likely to undergo surgery and less likely to receive chemotherapy and radiotherapy, and had better overall mean survival (2.5 vs 1.4 years). This survival advantage persisted in the multivariable Cox model (HR=0.69, 95%CI: 0.60, 0.78), despite adjustment for many factors including stage, grade and clinical interventions.Conclusions:This study provides evidence that EA cases occurring among individuals previously diagnosed with BE are different from the large majority of EA cases that occur without a prior BE diagnosis. Regardless of whether these differences emanate from aetiology, biology and/or selection biases, they underscore the importance of a prudent approach in using knowledge from EAC case–control studies in the management of BE populations.

MicroRNA Expression Signatures During Malignant Progression From Barrett's Esophagus.

The rapid increase and poor survival of esophageal adenocarcinoma (EAC) have led to significant efforts to promote early detection. Given that the premalignant lesion of Barrett's esophagus (BE) is the major known risk factor for EAC, multiple investigators have studied biomarker signatures that can predict malignant progression of BE to EAC. MicroRNAs, a novel class of gene regulators, are small non-coding RNAs and have been associated with carcinogenesis. MicroRNAs are ideal biomarkers because of their remarkable stability in fixed tissues, a common method for collection of clinical specimens, and in blood either within exosomes or as microRNA-protein complexes. Multiple studies show potential of microRNAs as tissue and blood biomarkers for diagnosis and prognosis of EAC but the results need confirmation in prospective studies. Although head-to-head comparisons are lacking, microRNA panels require less genes than messenger RNA panels for diagnosis of EAC in BE. MicroRNA diagnostic panels will need to be compared for accuracy against global measures of genome instability that were recently shown to be good predictors of progression but require sophisticated analytic techniques. Early studies on blood microRNA panels are promising but have found microRNA markers to be inconsistent among studies. MicroRNA expression in blood is different between various microRNA sub-compartments such as exosomes and microRNA-protein complexes and could affect blood microRNA measurements. Further standardization is needed to yield consistent results. We have summarized the current understanding of the tissue and blood microRNA signatures that may predict the development and progression of EAC.

LYN, a Key Gene From Bioinformatics Analysis, Contributes to Development and Progression of Esophageal Adenocarcinoma.

BackgroundEsophageal adenocarcinoma is a lethal malignancy whose incidence is rapidly growing in recent years. Previous reports suggested that Barrett’s esophagus (BE), which is represented by metaplasia-dysplasia-carcinoma transition, is regarded as the premalignant lesion of esophageal neoplasm. However, our knowledge about the development of esophageal adenocarcinoma is still very limited.Material/MethodsIn order to acquire better understanding about the pathological mechanisms in this field, we obtained gene profiling data on BE, esophageal adenocarcinoma patients, and normal controls from the Gene Expression Omnibus (GEO) database. Bioinformatics analyses, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were conducted.ResultsOur results revealed that several pathways, such as the wound healing, complement, and coagulation pathways, were closely correlated with cancer development and progression. The mitogen-activated protein kinase (MAPK) pathway was discovered to be responsible for the predisposition stage of cancer; while response to stress, cytokine-cytokine receptor interaction, nod-like receptor signaling pathway, and ECM-receptor interaction were chief contributors of cancer progression. More importantly, we discovered in this study that LYN was a critical gene. It was found to be the key nodule of several significant biological networks, which suggests its close correlation with cancer initiation and progression.ConclusionsThese results provided more information on the mechanisms of esophageal adenocarcinoma, which enlightened our way to the clinical discovery of novel therapeutic makers for conquering esophageal cancer. Keywords: esophageal adenocarcinoma; LYN; Go analysis; KEGG pathway.

Abstract 837: Pathogenesis and progression of esophageal adenocarcinoma by prior diagnosis of Barrett's esophagus

Abstract The absolute risk of carcinogenic progression given Barrett's esophagus (BE) is low and a majority of esophageal adenocarcinoma (EA) cases are diagnosed at first endoscopy without having had a prior diagnosis of BE. Therefore the research field has largely utilized case-control study designs with the implicit assumption that each case-group assessed (reflux, BE, EA) is representative of that stage in a linear progression towards cancer. To test the assumption that EA cases are a homogeneous group and therefore research findings may contribute to evidence-based prevention programs for diagnosed BE populations, we conducted a case-case study comparing the clinical presentation, medical history and survival of EA patients with and without a prior diagnosis of BE in the SEER-Medicare database. Eligible EA cases were diagnosed at ages > = 68 years during 1994-2009. Exposures were captured for a 2 year period starting 3 years prior to diagnosis. There were 5,271 EA patients in this study, 87% (n = 4,609) of which lacked a previous diagnosis of BE (“EA-no prior BE”). In univariate case-case comparisons, patient characteristics (age, sex, race, etc.) were mostly similar with the exceptions that EA-prior BE cases had lower comorbidity scores and a higher average number of physician visits. Conversely, tumor and treatment characteristics were starkly different; EA-prior BE cases were typically diagnosed with lower stage, lower grade, smaller tumors, and were less likely to have metastatic disease. EA-prior BE cases were also more likely to receive surgery and less likely to receive chemotherapy and radiotherapy. Multivariable case-case comparisons of exposures evidenced positive associations of GERD, ever-cigarette smoking, hypertension, dyslipidemia, weight-loss, peptic ulcer, pernicious anemia/celiac disease, and irritable bowel disease each in relation to EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose, diabetes and depression did not differ between the case groups. EA-prior BE cases had better overall mean survival (2.5 vs. 1.4 years), particularly for localized disease (3.3 vs 2.3 years). Such a survival advantage persisted after adjustment for age at diagnosis, sex, race, education and registry (hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.48, 0.58). Further adjustment for stage, grade, tumor size, metastatic disease, surgery, chemotherapy, radiotherapy, & Charlson comorbidity score attenuated but did not diminish the association (HR = 0.70, 95%CI: 0.64, 0.78). In sum, our study provides evidence that EA cases occurring among patients previously diagnosed with BE are dramatically different from those that were not, differing in clinical presentation, medical history, and survival. These findings underscore the importance of a prudent approach when attempting to reconstruct the natural history of this malignancy with utility for cancer prevention. Citation Format: Michael B. Cook, Jennifer Drahos, Shannon Wood, Lindsey Enewold, Ruth Parsons, Neal D. Freedman, Philip R. Taylor, Winnie Ricker, Christian C. Abnet. Pathogenesis and progression of esophageal adenocarcinoma by prior diagnosis of Barrett's esophagus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 837. doi:10.1158/1538-7445.AM2015-837

Local Synthesis of Pepsin in Barrett's Esophagus and the Role of Pepsin in Esophageal Adenocarcinoma.

Despite widespread use of proton pump inhibitors (PPIs), the incidence of esophageal adenocarcinoma (EAC) continues to rise. PPIs reduce reflux acidity, but only transiently inactivate gastric enzymes. Nonacid reflux, specifically nonacid pepsin, contributes to carcinogenesis in the larynx. Given the carcinogenic potential of pepsin and inefficacy of PPIs to prevent EAC, the presence and effect of pepsin in the esophagus should be investigated. Normal and Barrett's biopsies from 8 Barrett's esophagus patients were collected for pepsin analysis via Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR). Human esophageal cells cultured from healthy patients were treated with pepsin (0.01-1 mg/mL; 1-20 hours), acid (pH 4)±pepsin (5 minutes); real-time RT-PCR, ELISA, and cell migration were assayed. Pepsin was detected in all 8 Barrett's and 4 of 8 adjacent normal specimens. Pepsinogen mRNA was observed in 22 Barrett's, but not in normal adjacent samples. Pepsin induced PTSG2 (COX-2) and IL-1β expression and cell migration in vitro. Pepsin is synthesized by metaplastic, Barrett's esophageal mucosa. Nonacid pepsin increases metrics of tumorigenicity in esophageal epithelial cells in vitro. These findings implicate refluxed and locally synthesized pepsin in development and progression of EAC and, in part, explain the inefficacy of PPIs in the prevention of EAC.

Esophageal adenocarcinoma and obesity: peritumoral adipose tissue plays a role in lymph node invasion.

Obesity is associated with cancer risk in esophageal adenocarcinoma (EAC). Adipose tissue directly stimulates tumor progression independently from body mass index (BMI), but the mechanisms are not fully understood. We studied the morphological, histological and molecular characteristics of peritumoral and distal adipose tissue of 60 patients with EAC, to investigate whether depot-specific differences affect tumor behavior. We observed that increased adipocyte size (a hallmark of obesity) was directly associated with leptin expression, angiogenesis (CD31) and lymphangiogenesis (podoplanin); however, these parameters were associated with nodal metastasis only in peritumoral but not distal adipose tissue of patients. We treated OE33 cells with conditioned media (CM) collected from cultured biopsies of adipose tissue and we observed increased mRNA levels of leptin and adiponectin receptors, as well as two key regulator genes of epithelial-to-mesenchymal transition (EMT): alpha-smooth muscle actin (α-SMA) and E-cadherin. This effect was greater in cells treated with CM from peritumoral adipose tissue of patients with nodal metastasis and was partially blunted by a leptin antagonist. Therefore, peritumoral adipose tissue may exert a direct effect on the progression of EAC by secreting depot-specific paracrine factors, and leptin is a key player in this crosstalk.

BTG3 upregulation induces cell apoptosis and suppresses invasion in esophageal adenocarcinoma.

B cell translocation gene 3 (BTG3) is a tumor suppressor by inhibiting cell proliferation, migration, and regulating cell cycle progression in several tumors. However, its role in esophageal adenocarcinoma (EAC) remains unknown. Here, we detected the expression of BTG3 in EAC tissues and subsequent progression. BTG3 expression was significant decreased in EAC tissues and cell lines detected by real-time RT-PCR and Western blot. Relationships of BTG3 with EAC clinicopathology were analyzed statistically. The decrease expression of BTG3 is associated with lymph node metastases. In vitro assay demonstrated that overexpression of BTG3 significantly suppressed colony formation and proliferation of EAC cells. The suppressed migration and invasion abilities found in BTG3-overexpressing EAC cells. Our findings suggested that BTG3 is suppressor in the progression of EAC.

Barrett Esophagus Interventions: Patient Preference

Prevention of progression to esophageal adenocarcinoma (EAC) is the “end game” of intervention strategies for patients with Barrett esophagus (BE).

Role of microbiota and Toll-like receptors in progression of esophageal adenocarcinoma (EAC) in a rat reflux model.

28 Background: The discovery of the link between H. pylori and gastric cancer may be the most direct proof that bacterial signaling and host response can result in carcinogenesis. Accumulating evidence supports that activation of the Toll-like receptor (TLR) signaling pathway by microbes is associated with the development of GI malignancies. Using the modified Levrat model of gastroduodenojejunal reflux which mimics the physiological and molecular sequence of human EAC in the rat, this study profiles the expression of genes central to TLR-mediated signal transduction as well as characterizes the esophageal microbiome across the spectrum of EAC development. Methods: Modified Levrat’s surgery induced chronic acid reflux in Sprague-Dawley’s with harvest of esophagus 40 weeks post-surgery. Macordissection of normal adjacent epithelium, Barrett’s esophagus (BE), dysplasia and EAC tumor was performed followed by RNA/DNA isolation. Five samples per group were selected for gene expression profiling on the Qiagen TLR Signaling Pathway PCR Array as well as microbiome analysis by IBIS technology. Validation of IBIS was performed by fluorescence in situ hybridization (FISH). Results: Gene expression analysis identified TLRs 1-3 and 6, 7, 9 as significantly upregulated in EAC compared to normal esophagus. TLR 1 and 5 were significantly upregulated in dysplasia. TLR 1 was significantly upregulated in BE and normal adjacent epithelium. Thirty seven genes involved in the TLR signaling pathway were dysregulated in EAC, 30 in dysplasia, 21 in BE and 23 in normal adjacent. IBIS analysis revealed a prevalence of E. coli in BE and EAC which was validated by FISH. Conclusions: Toll-like receptor (TLR) signaling pathway responses to E. coli may participate in the development of EAC. E. coli may be a potential risk factor for EAC requiring further clinical validation.

MiR-145 expression accelerates esophageal adenocarcinoma progression by enhancing cell invasion and anoikis resistance.

BackgroundCarcinoma of the esophagus has a high case fatality ratio and is now the 6th most common cause of cancer deaths in the world. We previously conducted a study to profile the expression of miRNAs in esophageal adenocarcinoma (EAC) pre and post induction therapy. Of the miRNAs differentially expressed post induction chemoradiation, miR-145, a known tumor suppressor miRNA, was upregulated 8-fold following induction therapy, however, its expression was associated with shorter disease-free survival. This unexpected result was explored in this current study.MethodsIn order to study the role of miR-145 in EAC, miRNA-145 was overexpressed in 3 EAC cell lines (OE33, FLO-1, SK-GT-4) and one ESCC cell line (KYSE-410). After validation of the expression of miR-145, hallmarks of cancer such as cell proliferation, resistance to chemotherapy drugs or anoikis, and cell invasion were analyzed.ResultsThere were no differences in cell proliferation and 5 FU resistance between miR145 cell lines and the control cell lines. miR-145 expression also had no effect on cisplatin resistance in two of three cell lines (OE33 and FLO-1), but miR-145 appeared to protect SK-GT-4 cells against cisplatin treatment. However, there was a significant difference in cell invasion, cell adhesion and resistance to anoikis. All three EAC miR-145 cell lines invaded more than their respective controls. Similarly, OE33 and SK-GT-4 miR-145 cell lines were able to survive longer in a suspension state.DiscussionWhile expression of miR-145 in ESCC stopped proliferation and invasion, expression of miR-145 in EAC cells enhanced invasion and anoikis resistance. Although more work is required to understand how miR-145 conveys these effects, expression of miR-145 appears to promote EAC progression by enhancing invasion and protection against anoikis, which could in turn facilitate distant metastasis.

An immunofluorescent method for characterization of Barrett's esophagus cells.

Esophageal adenocarcinoma (EAC) has an overall survival rate of less than 17% and incidence of EAC has risen dramatically over the past two decades. One of the primary risk factors of EAC is Barrett's esophagus (BE), a metaplastic change of the normal squamous esophagus in response to chronic heartburn. Despite the well-established connection between EAC and BE, interrogation of the molecular events, particularly altered signaling pathways involving progression of BE to EAC, are poorly understood. Much of this is due to the lack of suitable in vitro models available to study these diseases. Recently, immortalized BE cell lines have become commercially available allowing for in vitro studies of BE. Here, we present a method for immunofluorescent staining of immortalized BE cell lines, allowing in vitro characterization of cell signaling and structure after exposure to therapeutic compounds. Application of these techniques will help develop insight into the mechanisms involved in BE to EAC progression and provide potential avenues for treatment and prevention of EAC.

MicroRNAs in Barrett's esophagus: future prospects.

MicroRNAs in Barrett's esophagus: future prospects.

Antireflux Surgery for Esophageal Adenocarcinoma Prevention: Is it Worth it?

Barrett’s esophagus is considered a premalignant condition with an annual risk of progression to esophageal adenocarcinoma of 0.1% to 0.3%. Those patients who experience symptoms of reflux have a further increased rate of malignant transformation. Currently, management of gastroesophageal reflux disease consists of acid suppression therapy with antacids, histamine-2 blockers or proton pump inhibitors. Patients who fail medical management may consider antireflux surgery, namely fundoplication. Given the relationship between reflux, Barrett’s esophagus and esophageal adenocarcinoma, the question arises whether patients with Barrett’s esophagus would benefit from antireflux surgery as a primary cancer prevention strategy. Here, we discuss the benefits and risks of antireflux medications and antireflux surgery, and in so doing attempt to answer the question: Should antireflux surgery be recommended for patients with BE, solely for EAC prevention?

Anti-inflammatory Effect of Full-Length Adiponectin and Proinflammatory Effect of Globular Adiponectin in Esophageal Adenocarcinoma Cells

Adiponectin, an adipocyte-derived hormone with anti-inflammatory and antitumor activity, inhibits esophageal adenocarcinoma (EAC) cell proliferation and induces apoptosis. Chronic inflammation is a key process involved in initiation and progression of EAC, but the roles and mechanisms of adiponectin in inflammation have not been fully understood in EAC. We aimed to analyze the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on inflammatory factors' expression and explore the roles of ROS/NF-κB signaling pathway in adiponectin-regulated inflammation in EAC cells. It was found that f-Ad and g-Ad differently regulated both mRNA and protein levels of TNF-α, IL-8, and IL-6 in a dose-dependent manner in OE19 cells. g-Ad apparently induced TNF-α, IL-8, and IL-6 production, which was inhibited by PDTC or NAC, and increased intracellular ROS levels and NF-κB p65 activation, whereas f-Ad significantly suppressed production of inflammatory factors and NF-κB p65 activation and also decreased the intracellular ROS levels. In conclusion, the study demonstrated that g-Ad exerts a proinflammatory effect whereas f-Ad appears to induce an anti-inflammatory effect in a ROS/NF-κB-dependent manner in OE19 cells.

Adiponectin Modulates DCA-Induced Inflammation via the ROS/NF-Kappa B Signaling Pathway in Esophageal Adenocarcinoma Cells

Deoxycholic acid (DCA) promotes the development and progression of esophageal adenocarcinoma (EAC) by inducing inflammation. Adiponectin is reported to have anti-inflammatory and anti-tumor effects. This study investigated the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on DCA-induced inflammation, and investigated the involvement of the reactive oxygen species (ROS)/NF-κB signaling pathway in inflammation in EAC. OE19 cells were treated with DCA (50-300 μM) and/or f-Ad/g-Ad (10.0 μg/ml) or N-acetylcysteine (NAC). The viability of cells exposed to DCA was measured by use of the MTT assay. mRNA and protein levels of the inflammatory factors were examined by real-time PCR and ELISA. Intra-cellular ROS levels were determined by use of flow cytometry. Protein levels of total and p-NF-κB p65 were measured by western blot. DCA induced dose and time-dependent cytotoxicity. mRNA and protein expression of TNF-α, IL-8, and IL-6 in cells treated with DCA alone were up-regulated, and intra-cellular ROS and p-NF-κB p65 protein levels were also increased. g-Ad promoted inflammatory factor production, ROS levels, and p-NF-κB p65 protein expression whereas f-Ad had a suppressive effect. When combined with DCA, g-Ad enhanced the pro-inflammatory effect of DCA whereas f-Ad, similar to NAC, suppressed the effect. DCA has a pro-inflammatory effect in EAC. f-Ad has an anti-inflammatory effect whereas g-Ad seems to have a pro-inflammatory effect in an ROS/NF-κB p65-dependent manner. This indicates that f-Ad could be a potential anti-inflammatory reagent for cancer therapy.

Genome-wide methylation analysis shows similar patterns in Barrett’s esophagus and esophageal adenocarcinoma

Barrett's esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). To identify novel tumor suppressors involved in esophageal carcinogenesis and potential biomarkers for the malignant progression of BE, we performed a genome-wide methylation profiling of BE and EAC tissues. Using Illumina's Infinium HumanMethylation27 BeadChip microarray, we examined the methylation status of 27 578 CpG sites in 94 normal esophageal (NE), 77 BE and 117 EAC tissue samples. The overall methylation of CpG sites within the CpG islands was higher, but outside of the CpG islands was lower in BE and EAC tissues than in NE tissues. Hierarchical clustering analysis showed an excellent separation of NE tissues from BE and EAC tissues; however, the clustering of BE and EAC tissues was less clear, suggesting that methylation occurs early during the progression of EAC. We confirmed many previously reported hypermethylated genes and identified a large number of novel hypermethylated genes in BE and EAC tissues, particularly genes encoding ADAM (A Disintegrin And Metalloproteinase) peptidase proteins, cadherins and protocadherins, and potassium voltage-gated channels. Pathway analysis showed that a number of channel and transporter activities were enriched for hypermethylated genes. We used pyrosequencing to validate selected candidate genes and found high correlations between the array and pyrosequencing data (rho > 0.8 for each validated gene). The differentially methylated genes and pathways may provide biological insights into the development and progression of BE and become potential biomarkers for the prediction and early detection of EAC.

Abstract B10: Vorinostat exposure results in decreased lamin B1 expression and nuclear structure normalization in an in vitro model of esophageal adenocarcinoma progression

Abstract Esophageal adenocarcinoma (EA) has a poor prognosis with five-year survival rates ranging between 5% and 30%, depending on stage at diagnosis. Barrett's esophagus (BE) contributes to a 15-fold increased risk for EA and is thought to be caused by chronic acid reflux. BE is a multi-stage condition believed to progress through metaplasia to dysplasia and then to EA. The progression from normal squamous epithelium through BE to EA is characterized by genetic and epigenetic alterations, but little is known about their association with the gross morphological alterations, including nuclear structure, used for clinical diagnosis. Recent advances in epigenomics increasingly acknowledge the interplay between chromatin remodeling and the role of three-dimensional (3D) nuclear architecture in regulating gene expression. To unravel the epigenetic mediated links between the cytological and molecular scale alterations in BE progression, we systematically investigated the effects of the clinically available histone deacetylase (HDAC) inhibitor vorinostat on gene expression and 3D nuclear architecture using human cell lines representative of normal squamous (EPC2), metaplasia (CPA) and adenocarcinoma (FLO-1) of the esophageal epithelium. We assessed alterations in viability, gene expression, and three-dimensional (3D) nuclear morphology upon drug treatment. A 12-point, three-fold, serial dilution drug-dose-response (DDR) curve at 24, 48 and 72 hour time points indicated that FLO-1 cancer cells were most sensitive to the drug, with an IC50 value at 48 hours of 0.7928 μM, versus 7.536 μM for CPA and 21.49 μM for EPC2. FLO-1, but not CPA or EPC2, underwent apoptosis after 24 hours of vorinostat exposure as assessed by the Caspase 3/7 Glo. RT-qPCR to assess gene expression demonstrated that p21 (CDKN1A) was induced as expected in all cell lines, with FLO-1 showing the greatest induction. MGMT expression was also increased 12-fold in FLO-1 after vorinostat treatment. To understand the gross morphological correlates of vorinostat treatment in all cell lines, we used optical computed tomography to image untreated, DMSO-treated and vorinostat treated cells individually in 3D with sub-micron, isotropic spatial resolution. Quantitative 3D image analysis revealed a preferential normalization of nuclear structure of cancer and metaplastic cells after 48 hour treatment at the FLO-1 IC50 dose. FLO-1 cells showed markedly reduced cell and nuclear volumes and decreased chromatin clumpiness after vorinostat treatment. Similar morphological trends were present but less pronounced in CPA cells. EPC2 cells showed minimal changes in response to treatment. These morphological trends were accompanied by the expected increase in H3K9 acetylation, which was significant in FLO-1. However, the anticipated corresponding drop in H3K9me3 was not observed. FLO-1 expressed significantly more lamin B1, but not lamin B2 or lamin A/C, compared to the other cell lines. Lamin B1 was significantly reduced in FLO-1 after vorinostat treatment. These results support further exploration of vorinostat for the treatment of patients with BE and EA. Our data indicate that vorinostat sensitivity increases, with a corresponding increase in apoptosis, as cells progress from normal to esophageal adenocarcinoma. This increased sensitivity to the drug is accompanied by a normalization of nuclear architecture, including a reduction in lamin B1, in surviving abnormal cells after treatment. Citation Format: Vivek Nandakumar, Nanna Hansen, Kathryn Hernandez, Patti Senechal, Miranda Slaydon, Honor Glenn, Paul Davies, Roger H. Johnson, Kimberly J. Bussey, Deirdre R. Meldrum. Vorinostat exposure results in decreased lamin B1 expression and nuclear structure normalization in an in vitro model of esophageal adenocarcinoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B10.

Mo1852 Statin Use Reduces the Risk of Esophageal Cancer: A Meta-Analysis

Background and Aim: Chronic inflammation has an important role by generating reactive oxygen species (ROS) in the development and progression of esophageal adenocarcinoma(EAC). Deoxycholic acid (DCA), causing chronic inflammation, plays the most significant role in the development of carcinogenesis during reflux. But the pro-inflammation of DCA in EAC cells is unknown. Adiponectin has anti-inflammatory and anti-tumor effects, but the mechanism of adiponectin in inflammation has not been very clear, especially in the development and progression of EAC. In this study, we aimed to observe the effect of two different type adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on the inflammatory response induced by DCA in EAC. Methods: OE19 cells were treated with DCA(50~300μM) or(and) f-Ad/g-Ad(10.0μg/ml). The cell viability was measured using MTT assay. Inflammatory factors were assayed by real-time PCR and ELISA analysis. The intra-cellular ROS levels were assayed using Flow Cytometry technology. Phosphor-nuclear factor kappaB (p-NF-κB) p65 protein was measured by Western blot. Results: High dose DCA (≥200μM) could significantly induce cytotoxicity and upregulate both mRNA and protein level of inflammatory factors TNF-α, IL-8 and IL-6 compared to untreated control in EAC cells. DCA(200μM) could apparently induce the release of ROS and increasing of p-NF-κBp65 protein. f-Ad suppressed DCA-induced the production of TNF-α, IL-8 and IL6 cytokines. Additionally, f-Ad also decreased DCA-induced the production of ROS and the p-NF-κBp65 protein. In contrast, g-Ad might further enhance DCA-induced inflammatory factors TNF-α, IL-8 and IL-6 production, and also increase intra-cellular ROS levels and pNF-κBp65 protein expression generated by DCA. Therefore, different type adiponectin differently regulate DCA-induced the inflammatory response by changing the ROS levels through NF-κBp65 activation. Conclusion: DCA exerts pro-inflammatory effect in a ROSNF-κBp65 dependent manner in EAC cells. f-Ad has an anti-inflammatory effect, whereas g-Ad appears to have an pro-inflammatory effect via changing the intra-cellular ROS levels, indicating that f-Ad could be a new potential anti-inflammatory reagent for cancer therapy.

Mo1853 Genetic Linkage Predisposing to Familial Barrett's Esophagus (FBE)

Background and Aim: Chronic inflammation has an important role by generating reactive oxygen species (ROS) in the development and progression of esophageal adenocarcinoma(EAC). Deoxycholic acid (DCA), causing chronic inflammation, plays the most significant role in the development of carcinogenesis during reflux. But the pro-inflammation of DCA in EAC cells is unknown. Adiponectin has anti-inflammatory and anti-tumor effects, but the mechanism of adiponectin in inflammation has not been very clear, especially in the development and progression of EAC. In this study, we aimed to observe the effect of two different type adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on the inflammatory response induced by DCA in EAC. Methods: OE19 cells were treated with DCA(50~300μM) or(and) f-Ad/g-Ad(10.0μg/ml). The cell viability was measured using MTT assay. Inflammatory factors were assayed by real-time PCR and ELISA analysis. The intra-cellular ROS levels were assayed using Flow Cytometry technology. Phosphor-nuclear factor kappaB (p-NF-κB) p65 protein was measured by Western blot. Results: High dose DCA (≥200μM) could significantly induce cytotoxicity and upregulate both mRNA and protein level of inflammatory factors TNF-α, IL-8 and IL-6 compared to untreated control in EAC cells. DCA(200μM) could apparently induce the release of ROS and increasing of p-NF-κBp65 protein. f-Ad suppressed DCA-induced the production of TNF-α, IL-8 and IL6 cytokines. Additionally, f-Ad also decreased DCA-induced the production of ROS and the p-NF-κBp65 protein. In contrast, g-Ad might further enhance DCA-induced inflammatory factors TNF-α, IL-8 and IL-6 production, and also increase intra-cellular ROS levels and pNF-κBp65 protein expression generated by DCA. Therefore, different type adiponectin differently regulate DCA-induced the inflammatory response by changing the ROS levels through NF-κBp65 activation. Conclusion: DCA exerts pro-inflammatory effect in a ROSNF-κBp65 dependent manner in EAC cells. f-Ad has an anti-inflammatory effect, whereas g-Ad appears to have an pro-inflammatory effect via changing the intra-cellular ROS levels, indicating that f-Ad could be a new potential anti-inflammatory reagent for cancer therapy.

Mo1851 Adiponectin Modulates Inflammatory Factors Expression Induced by Deoxycholic Acid via Reactive Oxygen Species in Esophageal Adenocarcinoma Cells

Background and Aim: Chronic inflammation has an important role by generating reactive oxygen species (ROS) in the development and progression of esophageal adenocarcinoma(EAC). Deoxycholic acid (DCA), causing chronic inflammation, plays the most significant role in the development of carcinogenesis during reflux. But the pro-inflammation of DCA in EAC cells is unknown. Adiponectin has anti-inflammatory and anti-tumor effects, but the mechanism of adiponectin in inflammation has not been very clear, especially in the development and progression of EAC. In this study, we aimed to observe the effect of two different type adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on the inflammatory response induced by DCA in EAC. Methods: OE19 cells were treated with DCA(50~300μM) or(and) f-Ad/g-Ad(10.0μg/ml). The cell viability was measured using MTT assay. Inflammatory factors were assayed by real-time PCR and ELISA analysis. The intra-cellular ROS levels were assayed using Flow Cytometry technology. Phosphor-nuclear factor kappaB (p-NF-κB) p65 protein was measured by Western blot. Results: High dose DCA (≥200μM) could significantly induce cytotoxicity and upregulate both mRNA and protein level of inflammatory factors TNF-α, IL-8 and IL-6 compared to untreated control in EAC cells. DCA(200μM) could apparently induce the release of ROS and increasing of p-NF-κBp65 protein. f-Ad suppressed DCA-induced the production of TNF-α, IL-8 and IL6 cytokines. Additionally, f-Ad also decreased DCA-induced the production of ROS and the p-NF-κBp65 protein. In contrast, g-Ad might further enhance DCA-induced inflammatory factors TNF-α, IL-8 and IL-6 production, and also increase intra-cellular ROS levels and pNF-κBp65 protein expression generated by DCA. Therefore, different type adiponectin differently regulate DCA-induced the inflammatory response by changing the ROS levels through NF-κBp65 activation. Conclusion: DCA exerts pro-inflammatory effect in a ROSNF-κBp65 dependent manner in EAC cells. f-Ad has an anti-inflammatory effect, whereas g-Ad appears to have an pro-inflammatory effect via changing the intra-cellular ROS levels, indicating that f-Ad could be a new potential anti-inflammatory reagent for cancer therapy.