A global and physical mechanism of gastric cancer formation and progression.

Gastric cancer is regarded as a major health issue for human being nowadays. The Helicobacter pylori (H. pylori) infection has been found to accelerate the development of gastritis and gastric cancer. Significant efforts have been made towards the understanding of the biology of gastric cancer on both genetic and epigenetic levels. However the physical mechanism behind the gastric cancer formation is still elusive. In this study, we constructed a model for investigating gastric cancer formation by explored the gastric cancer landscape and the flow flux. We uncovered three stable state attractors on the landscape: normal, gastritis and gastric cancer. The definition of each attractor is based on the biological function and gene expression levels. The global stabilities and the switching processes were quantified through the barrier heights and dominant kinetic paths. To investigate the underlying mechanism of the process from normal through the gastritis to the gastric cancer caused by genetic or epigenetic factors, we simulate the oncogenesis of gastric cancer through changes of several gene regulation strengths and H. pylori infection. The simulated results can illustrate the developmental and metastasis process of gastric cancer. Different H. pylori infection degrees accelerating the process from gastritis to gastric cancer can be quantified. Then we applied global sensitivity analysis, one key gene and four key regulations were found. These results are consist with the experimental results and can be used to design the polygenic anti-cancer agents through multiple key genes or regulations. The landscape approach provides a physical and simple strategy for analyzing gastric cancer in a systematic and quantitative way. It also offers new insight into treatment strategy for gastric cancer by adjusting relevant polygenic genes and regulations.