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

• Published in: Molecular oncology Vol. 14; no. 11; pp. 2834 - 2852
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-11-2020; John Wiley and Sons Inc; Wiley
• Subjects: Acids; Aspirin; Cancer; Cholesterol; chronic inflammation; Diet; Drug development; Dysplasia; Experiments; Gallbladder; gallbladder cancer; gallstones; Inflammation; lithogenic diet; Medicin och hälsovetenskap; Metaplasia; Preneoplasia; St Louis Missouri; Chile; United States > US; dysplasia; lithogenic diet; gallbladder cancer; metaplasia; gallstones; chronic inflammation
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12766

A novel mouse model of gallbladder preneoplasia secondary to diet‐induced stones progresses in parallel with intense inflammation. Ezetimibe inhibits stone formation, inflammation, and metaplasia–dysplasia development. Aspirin does not reduce stone formation, however, ameliorates inflammation and preneoplasia onset (but only in a low‐cholesterol diet). This model recapitulates the metaplasia–dysplasia sequence observed in humans and is suitable for gallbladder carcinogenesis research.
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.