Cargando…

Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia

Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in su...

Descripción completa

Detalles Bibliográficos
Autores principales: Rosa, Lorena, Lobos‐González, Lorena, Muñoz‐Durango, Natalia, García, Patricia, Bizama, Carolina, Gómez, Natalia, González, Ximena, Wichmann, Ignacio A., Saavedra, Nicolás, Guevara, Francisca, Villegas, Jaime, Arrese, Marco, Ferreccio, Catterina, Kalergis, Alexis M., Miquel, Juan Francisco, Espinoza, Jaime A., Roa, Juan C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607176/
https://www.ncbi.nlm.nih.gov/pubmed/33326125
http://dx.doi.org/10.1002/1878-0261.12766
_version_ 1783604593666555904
author Rosa, Lorena
Lobos‐González, Lorena
Muñoz‐Durango, Natalia
García, Patricia
Bizama, Carolina
Gómez, Natalia
González, Ximena
Wichmann, Ignacio A.
Saavedra, Nicolás
Guevara, Francisca
Villegas, Jaime
Arrese, Marco
Ferreccio, Catterina
Kalergis, Alexis M.
Miquel, Juan Francisco
Espinoza, Jaime A.
Roa, Juan C.
author_facet Rosa, Lorena
Lobos‐González, Lorena
Muñoz‐Durango, Natalia
García, Patricia
Bizama, Carolina
Gómez, Natalia
González, Ximena
Wichmann, Ignacio A.
Saavedra, Nicolás
Guevara, Francisca
Villegas, Jaime
Arrese, Marco
Ferreccio, Catterina
Kalergis, Alexis M.
Miquel, Juan Francisco
Espinoza, Jaime A.
Roa, Juan C.
author_sort Rosa, Lorena
collection PubMed
description Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low‐ or a high‐cholesterol diet) in wild‐type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti‐inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high‐cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low‐cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti‐inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high‐risk populations.
format Online
Article
Text
id pubmed-7607176
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-76071762020-11-06 Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia Rosa, Lorena Lobos‐González, Lorena Muñoz‐Durango, Natalia García, Patricia Bizama, Carolina Gómez, Natalia González, Ximena Wichmann, Ignacio A. Saavedra, Nicolás Guevara, Francisca Villegas, Jaime Arrese, Marco Ferreccio, Catterina Kalergis, Alexis M. Miquel, Juan Francisco Espinoza, Jaime A. Roa, Juan C. Mol Oncol Research Articles Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low‐ or a high‐cholesterol diet) in wild‐type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti‐inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high‐cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low‐cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti‐inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high‐risk populations. John Wiley and Sons Inc. 2020-09-17 2020-11 /pmc/articles/PMC7607176/ /pubmed/33326125 http://dx.doi.org/10.1002/1878-0261.12766 Text en © 2020 Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Rosa, Lorena
Lobos‐González, Lorena
Muñoz‐Durango, Natalia
García, Patricia
Bizama, Carolina
Gómez, Natalia
González, Ximena
Wichmann, Ignacio A.
Saavedra, Nicolás
Guevara, Francisca
Villegas, Jaime
Arrese, Marco
Ferreccio, Catterina
Kalergis, Alexis M.
Miquel, Juan Francisco
Espinoza, Jaime A.
Roa, Juan C.
Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
title Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
title_full Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
title_fullStr Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
title_full_unstemmed Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
title_short Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
title_sort evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607176/
https://www.ncbi.nlm.nih.gov/pubmed/33326125
http://dx.doi.org/10.1002/1878-0261.12766
work_keys_str_mv AT rosalorena evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT lobosgonzalezlorena evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT munozdurangonatalia evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT garciapatricia evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT bizamacarolina evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT gomeznatalia evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT gonzalezximena evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT wichmannignacioa evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT saavedranicolas evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT guevarafrancisca evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT villegasjaime evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT arresemarco evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT ferrecciocatterina evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT kalergisalexism evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT miqueljuanfrancisco evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT espinozajaimea evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia
AT roajuanc evaluationofthechemopreventivepotentialsofezetimibeandaspirininanovelmousemodelofgallbladderpreneoplasia