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

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

doi:10.1016/j.ebiom.2019.10.038

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

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

Hormel Institute

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	145-156
Number of pages	12
Journal	EBioMedicine
Volume	49
DOIs	https://doi.org/10.1016/j.ebiom.2019.10.038
State	Published - Nov 2019

Bibliographical note

Funding Information:
Dr. Dong reports grants from Hormel Foundation, during the conduct of the study; Dr. Iyer reports grants from Exact Sciences, grants from Pentax Medical, grants from Intromedic, non-financial support from Medtronic , other from Medtronic, other from CSA Medical, during the conduct of the study; Dr. Limburg reports other from National Cancer Institute, during the conduct of the study; other from Exact Sciences, outside the submitted work.

Funding Information:
This work was supported by the Hormel Foundation (Z. Dong). This work was supported by the grants from Exact Sciences, Pentax Medical, and Intromedic (CP-0016-1 P.G. Iyer). This work was also supported by the National Cancer Institute , Division of Cancer Prevention (contracts HHSN261200421 and N01CN35000 to P.J. Limburg). The funding bodies played no role in study design, data collection, data analysis, interpretation, writing of the report.

Publisher Copyright:
© 2019 The Authors

Keywords

Acetylsalicylic acid
Barrett's esophagus
Esophageal adenocarcinoma
Thromboxane A2 pathway

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development",

abstract = "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 = "Acetylsalicylic acid, Barrett's esophagus, Esophageal adenocarcinoma, Thromboxane A2 pathway",

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

note = "Funding Information: Dr. Dong reports grants from Hormel Foundation, during the conduct of the study; Dr. Iyer reports grants from Exact Sciences, grants from Pentax Medical, grants from Intromedic, non-financial support from Medtronic , other from Medtronic, other from CSA Medical, during the conduct of the study; Dr. Limburg reports other from National Cancer Institute, during the conduct of the study; other from Exact Sciences, outside the submitted work. Funding Information: This work was supported by the Hormel Foundation (Z. Dong). This work was supported by the grants from Exact Sciences, Pentax Medical, and Intromedic (CP-0016-1 P.G. Iyer). This work was also supported by the National Cancer Institute , Division of Cancer Prevention (contracts HHSN261200421 and N01CN35000 to P.J. Limburg). The funding bodies played no role in study design, data collection, data analysis, interpretation, writing of the report. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = nov,

doi = "10.1016/j.ebiom.2019.10.038",

language = "English (US)",

volume = "49",

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T1 - Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development

AU - Zhang, Tianshun

AU - Wang, Qiushi

AU - Ma, Wei Ya

AU - Wang, Keke

AU - Chang, Xiaoyu

AU - Johnson, Michele L.

AU - Bai, Ruihua

AU - Bode, Ann M.

AU - Foster, Nathan R.

AU - Falk, Gary W.

AU - Limburg, Paul J.

AU - Iyer, Prasad G.

AU - Dong, Zigang

N1 - Funding Information: Dr. Dong reports grants from Hormel Foundation, during the conduct of the study; Dr. Iyer reports grants from Exact Sciences, grants from Pentax Medical, grants from Intromedic, non-financial support from Medtronic , other from Medtronic, other from CSA Medical, during the conduct of the study; Dr. Limburg reports other from National Cancer Institute, during the conduct of the study; other from Exact Sciences, outside the submitted work. Funding Information: This work was supported by the Hormel Foundation (Z. Dong). This work was supported by the grants from Exact Sciences, Pentax Medical, and Intromedic (CP-0016-1 P.G. Iyer). This work was also supported by the National Cancer Institute , Division of Cancer Prevention (contracts HHSN261200421 and N01CN35000 to P.J. Limburg). The funding bodies played no role in study design, data collection, data analysis, interpretation, writing of the report. Publisher Copyright: © 2019 The Authors

PY - 2019/11

Y1 - 2019/11

N2 - 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.

AB - 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.

KW - Acetylsalicylic acid

KW - Barrett's esophagus

KW - Esophageal adenocarcinoma

KW - Thromboxane A2 pathway

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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