Response to TNF-α Is Increasing Along with the Progression in Barrett’s Esophagus

Chemnitzer, Olga; Götzel, K; Maurer, Luisa; Dietrich, Arne; Eichfeld, U; Lyros, Orestis; Jansen-Winkeln, Boris; Hoffmeister, Albrecht; Gockel, Ines; Thieme, René

doi:10.1007/s10620-017-4821-6

Cited by 12 publications

(11 citation statements)

References 52 publications

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“…These findings suggest that antioxidant agents could be used to prevent progression in the Barrett’s sequence. Recently, we have shown a decreased Akt/PI3K-pathway activation and apoptosis induction in OE33 and OE19 cells by curcumin [ 17 ]. The Nrf2-mediated antioxidant targets were induced by binding of Nrf2 to promotor regions containing an antioxidant response element (ARE) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…This might reflect the inter-patient heterogeneity and therefore the limitation of analysis of cell culture systems. Nevertheless, the Barrett’s cell culture model used here represents all stages of the Barrett’s sequence and therefore is a very valuable model to investigate Barrett’s esophagus and Barrett’s carcinoma in vitro [ 17 ]. Treating EAC cells with 5-FU, which is a standard chemotherapeutic for EAC patients treated by FLOT [ 2 ], has shown a decrease in cellular viability in OE33 cells, while treatment with acidified conditions (pH 6 and pH 5.5) resulted in a decay of the 5-FU-mediated loss of cellular viability.…”

Section: Discussionmentioning

confidence: 99%

“…The metaplastic cell line CP-A (CRL-4027) and the high-grade dysplastic cell line CP-B (CRL-4028) were purchased from LGC Standards (Wesel, Germany) and cultured according to the manufacturer’s protocol, using MCDB 153 growth medium (Biochrom, Berlin, Germany). Esophageal adenocarcinoma cells OE33 (ECACC-96070808) and OE19 (ECACC-96071721) (Sigma-Aldrich, Taufkirchen, Germany) were cultured in RPMI-1640 medium (ThermoFisher, Darmstadt, Germany) supplemented with 10% fetal bovine serum (Sigma-Aldrich, Taufkirchen, Germany) [ 17 ]. The fetal human esophageal fibroblast cell line FEF3 [ 15 ] was cultured in DMEM (ThermoFisher, Darmstadt, Germany) supplemented with 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

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Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

Storz

Walther

Chemnitzer

et al. 2021

Cancers

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Chronic acid reflux causes cellular damage and inflammation in the lower esophagus. Due to these irritating insults, the squamous epithelium is replaced by metaplastic epithelium, which is a risk factor for the development of esophageal adenocarcinoma (EAC). In this study, we investigated the acid susceptibility in a Barrett’s cell culture in vitro model, using six cell lines, derived from squamous epithelium (EPC1 and EPC2), metaplasia (CP-A), dysplasia (CP-B), and EAC (OE33 and OE19) cells. Cells exposed to acidic pH showed a decreased viability dependent on time, pH, and progression status in the Barrett’s sequence, with the highest acid susceptibility in the squamous epithelium (EPC1 and EPC2), and the lowest in EAC cells. Acid pulsing was accompanied with an activation of the Nrf2/Keap1- and the NFκB-pathway, resulting in an increased expression of HO1—independent of the cellular context. OE33 showed a decreased responsiveness towards 5-FU, when the cells were grown in acidic conditions (pH 6 and pH 5.5). Our findings suggest a strong damage of squamous epithelium by gastroesophageal reflux, while Barrett’s dysplasia and EAC cells apparently exert acid-protective features, which lead to a cellular resistance against acid reflux.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

Storz

Walther

Chemnitzer

et al. 2021

Cancers

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“…A potential alternative pathway, which might be involved in the Wnt-signaling pathway activation along the progression of Barrett’s esophagus, is the NF-κB-pathway, triggered by an increased TNF-α-receptivity in the more advanced stages of Barrett’s esophagus [32–34]. Acid-dependent and inflammation-induced damage leads to progression of Barrett’s esophagus, which could potentially contribute to TNF-α-promoted tumor growth and metastasis via PI3K/Akt, GSK3β, and NF-κB [35, 36].…”

Section: Discussionmentioning

confidence: 99%

In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett’s sequence

et al. 2019

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Background An altered Wnt-signaling activation has been reported during Barrett’s esophagus progression, but with rarely detected mutations in APC and β-catenin (CTNNB1) genes. Methods In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3β was performed in an in vitro cell culture model of Barrett’s esophagus. Representing the Barrett’s sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC. Results A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett’s metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1–10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium. Conclusion Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett’s esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett’s progression and the underlying pathological mechanisms. Electronic supplementary material The online version of this article (10.1186/s12876-019-0957-5) contains supplementary material, which is available to authorized users.

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“…18,19 More than that, obesity, which is a high-risk factor for BE, can also up-regulate some inflammatory factors. Hypertrophic fat cells can lead to tissue hypoxia, which ultimately induces the up-expression of IL-6 and tumor necrosis factor α (TNF-α), 20 which can not only mediate the up-regulation of IL-8 expression, promote angiogenesis and migration of ECM by activating endothelial cells 21,22 but also increase the expression of β-catenin-mediated oncogene c-myc in BE epithelial cells.- 23 It is noteworthy that TNF-α expression increases with the progression of metaplastic-proliferative-adenocarcinoma sequences.…”

Section: Tumor Precursor Microenvironmentmentioning

confidence: 99%

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

Han¹,

Cao²,

Huang³

et al. 2020

CMAR

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Esophageal cancer (EC) is the sixth most deadly cancer, and its incidence is still increasing year by year. Although the researches on the molecular mechanisms of EC have been widely carried out and incremental progress has been made, its overall survival rate is still low. There is cumulative evidence showing that the esophageal microenvironment plays a vital role in the development of EC. In precancerous lesions of the esophagus, high-risk environmental factors can promote the development of precancerous lesions by inducing the production of inflammatory factors and the recruitment of immune cells. In the tumor microenvironment, tumor-promoting cells can inhibit anti-tumor immunity and promote tumor progression through a variety of pathways, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs), and regulatory T cells (Tregs). The formation of extracellular hypoxia and acidic microenvironment and the change of extracellular matrix stiffness are also important factors affecting tumor progression and metastasis. Simultaneously, primary tumor-derived cytokines and bone marrow-derived immune cells can also promote the formation of pre-metastasis niche of EC lymph nodes, which are beneficial to EC lymph node metastasis. Further research on the specific mechanism of these processes in the occurrence, development, and metastasis of each EC subtype will support us to grasp the overall pre-cancerous prevention, targeted treatment, and metastatic assessment of EC.

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Response to TNF-α Is Increasing Along with the Progression in Barrett’s Esophagus

Cited by 12 publications

References 52 publications

Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett’s sequence

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

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