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Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To i...

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Autores principales: Westra, Wytske M, Straub, Danielle, Milano, Francesca, Buttar, Navtej S, Wang, Kenneth K, Krishnadath, Kausilia K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113020/
https://www.ncbi.nlm.nih.gov/pubmed/34718471
http://dx.doi.org/10.1093/dote/doab072
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author Westra, Wytske M
Straub, Danielle
Milano, Francesca
Buttar, Navtej S
Wang, Kenneth K
Krishnadath, Kausilia K
author_facet Westra, Wytske M
Straub, Danielle
Milano, Francesca
Buttar, Navtej S
Wang, Kenneth K
Krishnadath, Kausilia K
author_sort Westra, Wytske M
collection PubMed
description INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. METHODS: After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. RESULTS: Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. CONCLUSION: In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.
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spelling pubmed-91130202022-05-18 Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model Westra, Wytske M Straub, Danielle Milano, Francesca Buttar, Navtej S Wang, Kenneth K Krishnadath, Kausilia K Dis Esophagus Original Article INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. METHODS: After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. RESULTS: Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. CONCLUSION: In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome. Oxford University Press 2021-10-28 /pmc/articles/PMC9113020/ /pubmed/34718471 http://dx.doi.org/10.1093/dote/doab072 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Westra, Wytske M
Straub, Danielle
Milano, Francesca
Buttar, Navtej S
Wang, Kenneth K
Krishnadath, Kausilia K
Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model
title Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model
title_full Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model
title_fullStr Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model
title_full_unstemmed Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model
title_short Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model
title_sort inhibition of the bmp pathway prevents development of barrett’s-associated adenocarcinoma in a surgical rat model
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113020/
https://www.ncbi.nlm.nih.gov/pubmed/34718471
http://dx.doi.org/10.1093/dote/doab072
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