Abstract

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract. Chile has one of the highest GBC mortality rates. The main risk factor for GBC is the presence of cholelithiasis. Most cases follow a histological progression from metaplasia to-dysplasia and-GBC. Numerous studies have associated chronic inflammation with the development of cancer. But in GBC, there are limited studies on this topic, which present only indirect evidence due to the inaccessibility to the organ and the impossibility to follow-up the disease once the gallbladder has been removed. Nonetheless, it is accepted that chronic inflammation is the first step of metaplasia-dysplasia-GBC sequence. There are no consistent studies to confirm this hypothesis. We have developed a murine GBC model that mimics human GBC progression from gallstone disease developed by high-fat-diet consumption. Mice were divided as control group (low-cholesterol-diet) and D-Lit group (high-fat-diet). Nine and eight D-Lit mice were euthanized at 3 and 9 month of diet. 100% of D-Lit mice developed gallstones. Further, 100% D-Lit mice (8/8) developed pseudopyloric metaplasia and 50% (4/8) developed dysplasia at 9 month-diet while at 3 month-diet only 44% developed metaplasia. Then, we measured ex vivo the systemic immune cellular changes induced by each diet. We found that CD4+FoxP3+IL-10+ T cells, showed a significant increase in Treg population and also, interstitial macrophages and dendritic cells CD103+ increased in D-Lit mice. This is the first time that a GBC mouse model is generated from gallstone disease, where metaplasia-dysplasia-GBC can be followed. Research supported by FONDECYT grants 1130204 and 11140204, CONICYT Basal CCTE PFB16 and CONICYT PhD grant 21140027.