The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion.

Accumulating evidence has indicated that the inflammatory response is important for tumor promotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation-associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E (PGE) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis. The inflammatory response in the stroma induces TNF-α signaling in tumor cells, and the NOX1/ROS signaling pathway is activated downstream. In addition, the inflammatory pathway induces the expression of TLR2 in tumor epithelial cells. Both the NOX1/ROS and TLR2 pathways in tumor cells contribute to the acquisition and maintenance of stemness, which is an important tumor-promoting mechanism stimulated by inflammation. We also found that inflammation promotes malignant processes, like submucosal invasion, of TGF-β signaling-suppressed tumor cells through the activation of MMP2 protease. Moreover, we showed that mutant p53 induces innate immune and inflammatory signaling in the tumor stroma by a gain-of-function mechanism of mutant p53, which may explain the "cancer-induced inflammation" mechanism. These results indicate that the regulation of the inflammatory microenvironment via the inhibition of the COX-2/PGE and TLR/MyD88 pathways in combination will be an effective preventive or therapeutic strategy against gastrointestinal cancer development and malignant progression, especially those carrying p53 gain-of-function mutations.