Preclinical models for the study of Barrett's carcinogenesis

Read, Matthew; Krishnadath, Kausilia K.; Clemons, Nicholas J.; Phillips, Wayne A.

doi:10.1111/nyas.13916

Cited by 3 publications

(1 citation statement)

References 68 publications

(188 reference statements)

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“…In addition to GERD and BE, epidemiology studies have identified male gender, tobacco smoking and obesity as risk factors for EAC [14]. To investigate the causality and to delineate the molecular mechanisms of GERD, surgical rodent models have been reported [15], but with high mortality rates due to the challenging surgeries. An alternative approach using dietary intervention was reported by Quante et al [16], using 0.2% deoxycholic acid (DCA) in drinking water as a mimic of GERD to induce Barrett's-like metaplasia in interleukin 1β transgenic mice.…”

Section: Introductionmentioning

confidence: 99%

Chronic High-Fat Diet Induces Early Barrett’s Esophagus in Mice through Lipidome Remodeling

et al. 2020

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Esophageal adenocarcinoma (EAC) incidence has been rapidly increasing, potentially associated with the prevalence of the risk factors gastroesophageal reflux disease (GERD), obesity, high-fat diet (HFD), and the precursor condition Barrett’s esophagus (BE). EAC development occurs over several years, with stepwise changes of the squamous esophageal epithelium, through cardiac metaplasia, to BE, and then EAC. To establish the roles of GERD and HFD in initiating BE, we developed a dietary intervention model in C57/BL6 mice using experimental HFD and GERD (0.2% deoxycholic acid, DCA, in drinking water), and then analyzed the gastroesophageal junction tissue lipidome and microbiome to reveal potential mechanisms. Chronic (9 months) HFD alone induced esophageal inflammation and metaplasia, the first steps in BE/EAC pathogenesis. While 0.2% deoxycholic acid (DCA) alone had no effect on esophageal morphology, it synergized with HFD to increase inflammation severity and metaplasia length, potentially via increased microbiome diversity. Furthermore, we identify a tissue lipid signature for inflammation and metaplasia, which is characterized by elevated very-long-chain ceramides and reduced lysophospholipids. In summary, we report a non-transgenic mouse model, and a tissue lipid signature for early BE. Validation of the lipid signature in human patient cohorts could pave the way for specific dietary strategies to reduce the risk of BE in high-risk individuals.

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Section: Introductionmentioning

confidence: 99%

Chronic High-Fat Diet Induces Early Barrett’s Esophagus in Mice through Lipidome Remodeling

et al. 2020

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Inhibition of BMP2 and BMP4 Represses Barrett’s Esophagus While Enhancing the Regeneration of Squamous Epithelium in Preclinical Models

Correia

Straub

Read

et al. 2023

Cellular and Molecular Gastroenterology and Hepatology

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Novel In Vivo Mouse Cryoablation Model to Explore Unique Therapeutic Approaches for Premalignant Columnar Lesions

Correia

Straub

Calpe

et al. 2021

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Patients with epithelial metaplasias have an increased risk of developing malignancies. In Barrett’s esophagus, neo-columnar epithelium develops proximal to the squamous-columnar junction (SCJ) in the esophagus as the result of prolonged exposure to bile and acid reflux. Patients require lifetime periodic surveillance, due to lack of effective eradication therapies. The shortage of innovative treatment options is mostly attributable to the paucity of adequate in vivo models of neo-columnar epithelium regeneration. This protocol describes the generation of a cryoablation model to study regeneration of neo-epithelia at the SCJ. Cryoablation of the columnar and squamous mucosa at the SCJ was achieved through local application of liquid N2O in wild-type and reporter mice in combination with acid suppression. Acid suppression alone, showed restoration of the SCJ with normal histological features of both the neo-columnar and neo-squamous epithelium within 14 days. As a proof of principle, mice were treated with mNoggin, an inhibitor of bone morphogenetic proteins (BMPs), which are involved in the development of columnar epithelia. Local application of mNoggin to the ablated area at the SCJ significantly reduced the development of the neo-columnar mucosa. Although this model does not faithfully recapitulate the exact characteristics of Barrett’s esophagus, it is a well-suited tool to study the mechanisms of therapeutic inhibition of neo-columnar regeneration. It therefore represents an efficient and easy platform to test novel pharmacological therapies for treatment of neo-epithelial lesions at the SCJ.

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Preclinical models for the study of Barrett's carcinogenesis

Cited by 3 publications

References 68 publications

Chronic High-Fat Diet Induces Early Barrett’s Esophagus in Mice through Lipidome Remodeling

Chronic High-Fat Diet Induces Early Barrett’s Esophagus in Mice through Lipidome Remodeling

Inhibition of BMP2 and BMP4 Represses Barrett’s Esophagus While Enhancing the Regeneration of Squamous Epithelium in Preclinical Models

Novel In Vivo Mouse Cryoablation Model to Explore Unique Therapeutic Approaches for Premalignant Columnar Lesions

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