High inorganic phosphate may facilitate lung tumorigenesis at an early stage in K-rasLA1 mice

Abstract

Inorganic phosphate (Pi) is necessary for all living organisms because it affects the development of organs such as the bones, muscles, brains, and lungs by controlling several pivotal genes and regulating signal transduction. The aim of this study was to utilize a high phosphate diet (HPD) to determine, the concentration effects Pi-mediated signaling at different time intervals, in an in vivo system. Experiments were performed with K-rasLA1 lung cancer model mice. Mice were fed a normal diet (ND) containing 0.3% Pi and a high phosphate diet (HPD) containing 1% Pi for 1, 2 and 4 months. At the end of the experiment, all mice were sacrificed and were subjected to ICP-MS/OES, LA-ICP-MS analyses, Western blot, histopathological examination, immunohistochemistry (IHC), and immunofluorescence (IF) labeling. Results indicated that HPD accelerated tumorigenesis, and adenoma and adenocarcinoma incidence and tumor size increased significantly. However, at 4 months into the HPD using the K-ras LA1 lung cancer model, we observed suspended proliferation, massive ion level changes in the liver and lungs, energy generation via the tri-carboxylic acid (TCA) cycle in the liver, increased autophagy, and decreased angiogenesis and apoptosis. Taken together, these results indicate that HPD facilitates lung cancer promotion at an early stage of cancer development but after 4 months of HPD, tumorigenesis appears to slow down due to metabolic adaptation resulting in quiescence, which can cause severe cancer promotion in later stages. Therefore, carefully regulated Pi consumption might a critical role in lung cancer prevention.