Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer?

Abstract

ObjectivesTo analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts.Methodsp48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro. Two resources were employed to analyze the risk of pancreatic cancer in human subjects with PPI use.ResultsSerum gastrin levels were increased 8-fold (P < 0.0001) in mice treated with chronic high-dose PPIs, and this change correlated with an increase (P = 0.02) in PanIN grade and the development of microinvasive cancer. The CCK-2R expression was regulated by microRNA-148a in the p48-Cre/LSL-KrasG12D mice pancreas and in human pancreatic cancer cells in vitro. Proton pump inhibitor consumption in human subjects was correlated with pancreatic cancer risk (odds ratio, 1.54). A validation analysis conducted using the large-scale United Kingdom Biobank database confirmed the correlation (odds ratio, 1.9; P = 0.00761) of pancreatic cancer risk with PPI exposure.ConclusionsThis investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.

Does proton pump inhibitors use increase risk of digestive tumors?: A 2-sample Mendelian randomization study

“…[ 17 ] According to Matthew A Huber et al, hypergastrinemia resulting from PPIs could be the cause of pancreatic intraepithelial neoplasia and pancreatic malignancies, and this hypothesis was confirmed through animal experiments. [ 18 ] PPIs might increase the risk of digestive system tumor occurrence by elevating blood gastrin concentration, increasing nitrite concentration, and enhancing the toxicity of chemotherapy drugs. Conversely, PPIs could act as a protective factor for digestive system tumors by modifying the tumor microenvironment, regulating tumor cell pH value, promoting tumor cell apoptosis, inhibiting tumor cell growth, improving tumor cell drug resistance, and other functions.…”