Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma developmentResearch in context

Tianshun Zhang; Qiushi Wang; Wei-Ya Ma; Keke Wang; Xiaoyu Chang; Michele L. Johnson; Ruihua Bai; Ann M. Bode; Nathan R. Foster; Gary W. Falk; Paul J. Limburg; Prasad G. Iyer; Zigang Dong

EBioMedicine (Nov 2019)

Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma developmentResearch in context

Tianshun Zhang,
Qiushi Wang,
Wei-Ya Ma,
Keke Wang,
Xiaoyu Chang,
Michele L. Johnson,
Ruihua Bai,
Ann M. Bode,
Nathan R. Foster,
Gary W. Falk,
Paul J. Limburg,
Prasad G. Iyer,
Zigang Dong

Affiliations

Tianshun Zhang: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States
Qiushi Wang: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States
Wei-Ya Ma: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States
Keke Wang: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States
Xiaoyu Chang: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States
Michele L. Johnson: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Avenue SW, Rochester, MN 55905, United States
Ruihua Bai: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States; The Affiliated Cancer Hospital of Zhengzhou University, No.127 Dongming Road, Henan 450000 China
Ann M. Bode: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States
Nathan R. Foster: Department of Health Sciences Research, Mayo Clinic, 200 First Avenue SW, Rochester, MN 55905, United States
Gary W. Falk: Department of Medicine, University of Pennsylvania, 749 Perelman Center for Advanced Medicine, South Pavilion, Philadelphia, PA 19104, United States
Paul J. Limburg: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Avenue SW, Rochester, MN 55905, United States
Prasad G. Iyer: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Avenue SW, Rochester, MN 55905, United States
Zigang Dong: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States; Corresponding author.

Journal volume & issue: Vol. 49
pp. 145 – 156

Abstract

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Background: Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. Methods: Patient biopsy samples were evaluated for COX1/2, and thromboxane A2 synthase (TBXAS) expression. Circulating prostaglandins biosynthesis was determined using enzyme immunoassay kits. Anchorage-independent cell growth assay, crystal violet staining assay, and xenograft experiments were conducted to assess BE and EAC cell growth. A surgical mouse model of reflux (i.e., esophagoduodenostomy) was established and samples were analyzed using an enzyme immunoassay kit, immunohistochemistry, immunoblotting, or RT-PCR. Esophageal biopsy samples (pre- and post-intervention) were obtained from a randomized clinical trial in which participants were administered esomeprazole (40 mg) twice daily in combination with an acetylsalicylic acid (ASA) placebo or 81 or 325 mg ASA for 28 days. Esophageal biopsy specimens before and after the intervention period were analyzed. Findings: COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels. ASA suppressed BE and EAC growth by targeting the TXA2 pathway. Additionally, biopsies from 49 patients (with similar baseline characteristics) showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation. Interpretation: This study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. Funding: Hormel Foundation, Exact Sciences, Pentax Medical, Intromedic and National Cancer. Keywords: Thromboxane A2 pathway, Acetylsalicylic acid, Barrett's esophagus, Esophageal adenocarcinoma

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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