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Cancer Risk in Barrett’s Esophagus
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Cancer Risk in Barrett’s Esophagus

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 9038

Special Issue Editor

Dr. Nikki Johnston

E-Mail Website
Guest Editor
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226, USA
Interests: otolaryngology; microbiology and immunology; reflux; pepsin; reflux-attributed inflammatory and neoplastic disease; cell culture; cancer biology; gene and protein expression; drug development

Special Issue Information

Dear Colleagues, 

Esophageal adenocarcinoma (EAC) incidence has risen faster than any other cancer in the United States since the 1970s. With a 5-year survival of <20%, it claims the highest mortality rate among US cancers. Primary risk factors for EAC include gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), and to lesser extent obesity, smoking, and low fruit and vegetable intake. Surprisingly little is known of the molecular events and progenitor cells involved in the progression of BE to EAC. Acid has historically been considered the most damaging element in gastric reflux, and acid-suppressing Proton Pump Inhibitors (PPIs) are the most common medical therapy for GERD. However, evidence for their cancer preventive benefit is inconclusive. Large population studies and meta-analyses have demonstrated a direct association between PPI use and EAC risk, and evidence supports a range of possible mechanisms by which PPIs may contribute to carcinogenesis. In this Special Issue, we invite research articles, review articles as well as communications on the molecular biology and pathophysiology of BE that could improve diagnostic and therapeutic modalities in the armamentarium for BE to prevent progression to EAC.

Dr. Nikki Johnston
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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Research

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17 pages, 2401 KiB  
Article
Topical Alginate Protection against Pepsin-Mediated Esophageal Damage: E-Cadherin Proteolysis and Matrix Metalloproteinase Induction
by Tina L. Samuels, Simon Blaine-Sauer, Ke Yan, Kate Plehhova, Cathal Coyle and Nikki Johnston
Int. J. Mol. Sci. 2023, 24(9), 7932; https://doi.org/10.3390/ijms24097932 - 27 Apr 2023
Cited by 1 | Viewed by 1603
Abstract
Epithelial barrier dysfunction is a hallmark of gastroesophageal reflux disease (GERD) related to symptom origination, inflammatory remodeling and carcinogenesis. Alginate-based antireflux medications were previously shown to topically protect against peptic barrier disruption, yet the molecular mechanisms of injury and protection were unclear. Herein, [...] Read more.
Epithelial barrier dysfunction is a hallmark of gastroesophageal reflux disease (GERD) related to symptom origination, inflammatory remodeling and carcinogenesis. Alginate-based antireflux medications were previously shown to topically protect against peptic barrier disruption, yet the molecular mechanisms of injury and protection were unclear. Herein, Barrett’s esophageal (BAR-T) cells were pretreated with buffered saline (HBSS; control), dilute alginate medications (Gaviscon Advance or Gaviscon Double Action, Reckitt Benckiser), a viscosity-matched placebo, or ADAM10 and matrix metalloproteinase (MMP) inhibitors before exposure to HBSS pH7.4 or pH4 ± 1 mg/mL pepsin for 10–60 min. Cell viability was assessed by ATP assay; mediators of epithelial integrity, E-cadherin, ADAM10, and MMPs were examined by Western blot and qPCR. Alginate rescued peptic reduction of cell viability (p < 0.0001). Pepsin-pH4 yielded E-cadherin fragments indicative of regulated intramembrane proteolysis (RIP) which was not rescued by inhibitors of known E-cadherin sheddases. Transcriptional targets of E-cadherin RIP fragments were elevated at 24 h (MMP-1,2,9,14; p < 0.01). Alginate rescued E-cadherin cleavage, ADAM10 maturation, and MMP induction (p < 0.01). Results support RIP as a novel mechanism of peptic injury during GERD. Alginate residue after wash-out to mimic physiologic esophageal clearance conferred lasting protection against pepsin-induced molecular mechanisms that may exacerbate GERD severity and promote carcinogenesis in the context of weakly acidic reflux. Full article
(This article belongs to the Special Issue Cancer Risk in Barrett’s Esophagus)
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12 pages, 1422 KiB  
Article
The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes
by Simon Blaine-Sauer, Tina L. Samuels, Ke Yan and Nikki Johnston
Int. J. Mol. Sci. 2023, 24(7), 6765; https://doi.org/10.3390/ijms24076765 - 5 Apr 2023
Cited by 2 | Viewed by 2937
Abstract
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs [...] Read more.
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes. Full article
(This article belongs to the Special Issue Cancer Risk in Barrett’s Esophagus)
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Review

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0 pages, 920 KiB  
Review
Epigenetic Alterations from Barrett’s Esophagus to Esophageal Adenocarcinoma
by Pelin Ergun, Sezgi Kipcak and Serhat Bor
Int. J. Mol. Sci. 2023, 24(9), 7817; https://doi.org/10.3390/ijms24097817 - 25 Apr 2023
Cited by 1 | Viewed by 1406
Abstract
Barrett’s esophagus (BE) is a disease entity that is a sequela of chronic gastroesophageal reflux disease that may result in esophageal adenocarcinoma (EAC) due to columnar epithelial dysplasia. The histological degree of dysplasia is the sole biomarker frequently utilized by clinicians. However, the [...] Read more.
Barrett’s esophagus (BE) is a disease entity that is a sequela of chronic gastroesophageal reflux disease that may result in esophageal adenocarcinoma (EAC) due to columnar epithelial dysplasia. The histological degree of dysplasia is the sole biomarker frequently utilized by clinicians. However, the cost of endoscopy and the fact that the degree of dysplasia does not progress in many patients with BE diminish the effectiveness of histological grading as a perfect biomarker. Multiple or more quantitative biomarkers are required by clinicians since early diagnosis is crucial in esophageal adenocancers, which have a high mortality rate. The presence of epigenetic factors in the early stages of this neoplastic transformation holds promise as a predictive biomarker. In this review, current studies on DNA methylations, histone modifications, and noncoding RNAs (miRNAs) that have been discovered during the progression from BE dysplasia to EAC were collated. Full article
(This article belongs to the Special Issue Cancer Risk in Barrett’s Esophagus)
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17 pages, 620 KiB  
Review
Cancer Risk in Barrett’s Esophagus: A Clinical Review
by Ahmed Sam Beydoun, Kaleigh A. Stabenau, Kenneth W. Altman and Nikki Johnston
Int. J. Mol. Sci. 2023, 24(7), 6018; https://doi.org/10.3390/ijms24076018 - 23 Mar 2023
Cited by 7 | Viewed by 2432
Abstract
Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence and is associated with a poor prognosis. Barrett’s esophagus (BE) is a known precursor of esophageal adenocarcinoma. This review aims to explore Barrett’s esophagus, esophageal adenocarcinoma, and the progression from the former to the latter. [...] Read more.
Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence and is associated with a poor prognosis. Barrett’s esophagus (BE) is a known precursor of esophageal adenocarcinoma. This review aims to explore Barrett’s esophagus, esophageal adenocarcinoma, and the progression from the former to the latter. An overview of the definition, diagnosis, epidemiology, and risk factors for both entities are presented, with special attention being given to the areas of debate in the literature. The progression from Barrett’s esophagus to esophageal adenocarcinoma is reviewed and the relevant molecular pathways are discussed. The definition of Barrett’s esophagus remains debated and without international consensus. This, alongside other factors, has made establishing the true prevalence of Barrett’s esophagus challenging. The degree of dysplasia can be a histological challenge, but is necessary to guide clinical management. The progression of BE to EAC is likely driven by inflammatory pathways, pepsin exposure, upregulation of growth factor pathways, and mitochondrial changes. Surveillance is maintained through serial endoscopic evaluation, with shorter intervals recommended for high-risk features. Full article
(This article belongs to the Special Issue Cancer Risk in Barrett’s Esophagus)
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