Turning Skyscrapers into Town Houses: Insights into Barrett's Esophagus

Ahrens, Theresa D.; Lutz, Lisa; Laßmann, Silke; Werner, Martin

doi:10.1159/000447779

Cited by 7 publications

(5 citation statements)

References 95 publications

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“…Human BE is a pathological condition associated with longstanding GERD and is defined as metaplasia of the flat, layered esophageal squamous epithelium into a tall intestinal columnar epithelial cells [23,25]. It is important to highlight that Barrett's metaplasia may originate from GEJ stem cells [26,27].…”

Section: Discussionmentioning

confidence: 99%

“…However, many ongoing controversies and challenges and potential mediators responsible for the development of BE still remain unsolved. Additionally, the conversion process of normal squamous epithelium towards Barrett's metaplasia is difficult to monitor directly under clinical conditions [23]. Thus, over the last few years, several experimental models using various types of cell cultures and animal models have been published to investigate the mechanisms of bile and/or acid exposure in BE pathogenesis [1,23].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Profile of Barrett’s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies

Korbut

Janmaat

Wierdak

et al. 2020

IJMS

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Barrett’s esophagus (BE) is a premalignant condition caused by gastroesophageal reflux disease (GERD), where physiological squamous epithelium is replaced by columnar epithelium. Several in vivo and in vitro BE models were developed with questionable translational relevance when implemented separately. Therefore, we aimed to screen Gene Expression Omnibus 2R (GEO2R) databases to establish whether clinical BE molecular profile was comparable with animal and optimized human esophageal squamous cell lines-based in vitro models. The GEO2R tool and selected databases were used to establish human BE molecular profile. BE-specific mRNAs in human esophageal cell lines (Het-1A and EPC2) were determined after one, three and/or six-day treatment with acidified medium (pH 5.0) and/or 50 and 100 µM bile mixture (BM). Wistar rats underwent microsurgical procedures to generate esophagogastroduodenal anastomosis (EGDA) leading to BE. BE-specific genes (keratin (KRT)1, KRT4, KRT5, KRT6A, KRT13, KRT14, KRT15, KRT16, KRT23, KRT24, KRT7, KRT8, KRT18, KRT20, trefoil factor (TFF)1, TFF2, TFF3, villin (VIL)1, mucin (MUC)2, MUC3A/B, MUC5B, MUC6 and MUC13) mRNA expression was assessed by real-time PCR. Pro/anti-inflammatory factors (interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, tumor necrosis factor α, interferon γ, granulocyte-macrophage colony-stimulating factor) serum concentration was assessed by a Luminex assay. Expression profile in vivo reflected about 45% of clinical BE with accompanied inflammatory response. Six-day treatment with 100 µM BM (pH 5.0) altered gene expression in vitro reflecting in 73% human BE profile and making this the most reliable in vitro tool taking into account two tested cell lines. Our optimized and established combined in vitro and in vivo BE models can improve further physiological and pharmacological studies testing pathomechanisms and novel therapeutic targets of this disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Profile of Barrett’s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies

Korbut

Janmaat

Wierdak

et al. 2020

IJMS

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“…This group of proteins has characteristic expression patterns that in general decline during the progression from BE into EAC. The group includes MUC2, characteristically secreted by goblet cells; gastric MUC5AC, expressed at the surface epithelium and the submucosal glands; and MUC6 and MUC5B, found inside the glands [55][56][57]. Associated to mucins, too, is the family of trefoil factors, including the gastric tumor suppressors TFF1 and TTF2, which are co-localized with MUC5AC and MUC6, respectively; and TFF3, which is typically not secreted by gastric mucosa but, like MUC2, by goblet cells.…”

Section: Discussionmentioning

confidence: 99%

Alteration of protein expression and spliceosome pathway activity during Barrett’s carcinogenesis

et al. 2021

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Background Barrett’s esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challenged by problems such as inter-observer variability in the face of the high heterogeneity of dysplastic tissue. Molecular markers might offer an additional way to understand the carcinogenesis and improve the diagnosis—and eventually treatment. In this study, we probed significant proteomic changes during dysplastic progression from BE into EAC. Methods During endoscopic mucosa resection, epithelial and stromal tissue samples were collected by laser capture microdissection from 10 patients with normal BE and 13 patients with high-grade dysplastic/EAC. Samples were analyzed by mass spectrometry-based proteomic analysis. Expressed proteins were determined by label-free quantitation, and gene set enrichment was used to find differentially expressed pathways. The results were validated by immunohistochemistry for two selected key proteins (MSH6 and XPO5). Results Comparing dysplastic/EAC to non-dysplastic BE, we found in equal volumes of epithelial tissue an overall up-regulation in terms of protein abundance and diversity, and determined a set of 226 differentially expressed proteins. Significantly higher expressions of MSH6 and XPO5 were validated orthogonally and confirmed by immunohistochemistry. Conclusions Our results demonstrate that disease-related proteomic alterations can be determined by analyzing minute amounts of cell-type-specific collected tissue. Further analysis indicated that alterations of certain pathways associated with carcinogenesis, such as micro-RNA trafficking, DNA damage repair, and spliceosome activity, exist in dysplastic/EAC.

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“…The genes with logFC values >1 were considered to be significantly upregulated, and logFc values < −1 were considered to be downregulated. To evaluate the progression of BE and EAC within the in vitro models described below, 20 genes were selected ( SOCS3, SOX4, SOX9, SOX15, FZD5, KRT4, KRT8, KRT15, KRT18, PTGS1, PTGS2, TMEM2, IFNGR1, TIMP1, TNFRSF10B, IL1B, IL1R1, IL1RN, IL1A, NFKBIL1 ) as possible molecular markers of BE and EAC development based on a scientific literature screening, described in details in the Discussion section [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 92 , 93 , 94 ].…”

Section: Methodsmentioning

confidence: 99%

Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

Korbut

Krukowska

Magierowski

2022

IJMS

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The molecular processes that predispose the development of Barrett’s esophagus (BE) towards esophageal adenocarcinoma (EAC) induced by gastrointestinal reflux disease (GERD) are still under investigation. In this study, based on a scientific literature screening and an analysis of clinical datasets, we selected a panel of 20 genes covering BE- and EAC-specific molecular markers (FZD5, IFNGR1, IL1A, IL1B, IL1R1, IL1RN, KRT4, KRT8, KRT15, KRT18, NFKBIL1, PTGS1, PTGS2, SOCS3, SOX4, SOX9, SOX15, TIMP1, TMEM2, TNFRSF10B). Furthermore, we aimed to reflect these alterations within an experimental and translational in vitro model of BE to EAC progression. We performed a comparison between expression profiles in GSE clinical databases with an in vitro model of GERD involving a BE cell line (BAR-T) and EAC cell lines (OE33 and OE19). Molecular responses of cells treated with acidified bile mixture (BM) at concentration of 100 and 250 μM for 30 min per day were evaluated. We also determined a basal mRNA expression within untreated, wild type cell lines on subsequent stages of BE and EAC development. We observed that an appropriately optimized in vitro model based on the combination of BAR-T, OE33 and OE19 cell lines reflects in 65% and more the clinical molecular alterations observed during BE and EAC development. We also confirmed previous observations that exposure to BM (GERD in vitro) activated carcinogenesis in non-dysplastic cells, inducing molecular alternations in the advanced stages of BE. We conclude that it is possible to induce, to a high extent, the molecular profile observed clinically within appropriately and carefully optimized experimental models, triggering EAC development. This experimental scheme and molecular marker panel might be implemented in further research, e.g. aiming to develop and evaluate novel compounds and prodrugs targeting GERD as well as BE and EAC prevention and treatment.

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Turning Skyscrapers into Town Houses: Insights into Barrett's Esophagus

Cited by 7 publications

References 95 publications

Molecular Profile of Barrett’s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies

Molecular Profile of Barrett’s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies

Alteration of protein expression and spliceosome pathway activity during Barrett’s carcinogenesis

Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

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