Evaluation of the chemopreventive potentials of ezetimibeand aspirin in a novel mouse model of gallbladderpreneoplasia

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dc.contributor.authorRosa, Lorena
dc.contributor.authorLobos-González, Lorena
dc.contributor.authorMunoz Durango, Natalia
dc.contributor.authorGarcıa, Patricia
dc.contributor.authorBizama, Carolina
dc.contributor.authorGomez, Natalia
dc.contributor.authorGonzalez, Ximena
dc.contributor.authorWichmann, Ignacio A.
dc.contributor.authorSaavedra, Nicolas
dc.contributor.authorGuevara, Francisca
dc.contributor.authorVillegas, Jaime
dc.contributor.authorArrese, Marco
dc.contributor.authorFerreccio, Catterina
dc.contributor.authorAlexis M. Kalergis, Alexis M.
dc.contributor.authorMiquel, Juan Francisco
dc.contributor.authorEspinoza, Jaime A.
dc.contributor.authorRoa, Juan C.
dc.date.accessioned2021-10-27T15:08:10Z
dc.date.available2021-10-27T15:08:10Z
dc.date.issued2020
dc.description.abstractGallbladder 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.es
dc.identifier.citationMolecular Oncology Volume14, Issue11 November 2020 Pages 2834-2852es
dc.identifier.urihttps://doi.org/10.1002/1878-0261.12766es
dc.identifier.urihttp://hdl.handle.net/11447/4954
dc.language.isoen_USes
dc.subjectchronic inflammationes
dc.subjectdysplasiaes
dc.subjectgallbladdercanceres
dc.subjectgallstoneses
dc.subjectlithogenic dietes
dc.subjectmetaplasiaes
dc.titleEvaluation of the chemopreventive potentials of ezetimibeand aspirin in a novel mouse model of gallbladderpreneoplasiaes
dc.typeArticlees

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