Abstract 422: IL-10 inhibition accelerates gastric tumorigenesis in mice with either <i>Helicobacter pylori</i> infection or chronic alcohol intake
Authors: Faisal aziz, Ann Bode, Zigang Dong
Journal: Cancer Research (2020)

Abstract Background and Aims: H. pylori is a class I human carcinogen that contributes to the development of gastric cancer through complex interactions between genetic and environmental factors. Alcohol is also classified as a group 1 carcinogen and results in 3.3 million deaths every year. H. pylori infection and alcohol intake are risk factors in gastric carcinogenesis; however, no conclusive model or experimental evidence yet exists showing that a combination of H. pylori and alcohol increases the risk of gastric cancer. Hence, we hypothesized that alcohol and H. pylori infection alone cannot produce gastric cancer in human and mice but combination of both will produce gastric cancer. Here, we provide insight into the molecular mechanisms driving gastric carcinogenesis. Methods: Here, we developed a series of mouse models that progress from chronic gastritis to gastric cancer, induced by infecting H. pylori combined with chronic alcohol consumption and then determining the molecular mechanism of the progression C57-BL/6J-219 and IL-10 knockout mice were infected with the H. pylori (SS1) strain and then fed or not fed alcohol. Results: Here, we show that alcohol consumption in combination with H. pylori infection induce gastric cancer with the IL-10 downregulation through metabolic dysfunction in CD8+ cells. IL-10 knockout accelerates tumor development in mice with either H. pylori infection or alcohol induced gastric cancer or both. Specifically, we show IL-10 inhibits glucose uptake and glycolysis and promotes oxidative phosphorylation with lactate inhibition. Consequently, in the absence of IL-10 signaling, CD8+ cells accumulate damaged mitochondria in a mouse model of gastric cancer induced with the combination of alcohol plus H. pylori infection, and this result in mitochondrial dysfunction and production of IL-1β. Furthermore, downregulation of IL-10 and CD8+ cells switch to stimulate IL1β secretion that facilitates H. pylori colonization to gastric cancer cells and suppress NKX6.3 expression as well as cancer cells apoptosis. Overall, the molecular mechanisms of gastric carcinogenesis include IL-10 inhibition resulting in lowered host immunity via mitochondrial dysfunction of CD8+ lymphocytes; gastric inflammation due to H. pylori infection, alcohol intake, and IL-1β production; and disruption of gastric-specific tumor suppressor NKX6.3 expression, which increases cancer cell survival and proliferation. This is the first study providing evidence that a combination of H. pylori infection and alcohol consumption could lead to the development and progression of gastritis leading to gastric carcinogenesis. Conclusions: This study suggests that anti-inflammatory IL-10 cytokine stimulation could reduce the incidence of gastric cancer, along with lowered alcohol consumption and treatment of H. pylori infection. IL-10 may be a potential therapeutic target and its stimulation may be a novel therapeutic strategy for the treatment of alcohol-associated gastric cancer. Citation Format: Faisal aziz, Ann Bode, Zigang Dong. IL-10 inhibition accelerates gastric tumorigenesis in mice with either Helicobacter pylori infection or chronic alcohol intake [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 422.