O017 TLR2 promotes tumorigenesis independent of inflammation in STAT3-driven gastric cancer

Abstract

Introduction Cancer of the stomach (gastric cancer) is the second most lethal cancer world-wide, and represents a growing number of cancers that are associated with inflammation.While it is accepted that deregulated interactions between gastric microbes (i.e. Helicobacter pylori) and the host innate immune system are likely to be involved in the pathogenesis of gastric inflammation (gastritis) and cancer, the identity of oncogenic inflammatory/immune regulators in the host gastric mucosa remains obscure. On this note, deregulated activation of cytokine signaling pathways, especially the pro-inflammatory and oncogenic transcription factor signal transducer and activator of transcription (STAT) 3, is implicated in various inflammation-associated cancers, including up to 50% of human gastric cancers. However, the downstream molecular consequences of aberrant STAT3 activation in promoting carcinogenesis remain to be fully elucidated. Methods We report here our investigation into the role of Toll-like receptors (TLRs), which are key components of the innate immune system primarily known to trigger an inflammatory response upon pathogen detection, during gastric cancer. For this purpose, we used 2 independent gastritis/gastric cancer mouse models characterized by STAT3 hyper-activation, (1) gp130F/F mice carrying a specific knock-in mutation in the interleukin (IL)-6 cytokine family co-receptor gp130 which abolishes a negative feedback mechanism, and (2) K19-Wnt1/C2mE transgenic mice displaying the simultaneous activation of the cyclooxygenase-2, prostaglandin E2 and Wnt pathways. Results Among the TLR family, aberrant gastric STAT3 activation in these mice specifically caused a significant increase in the expression of TLR2. Genetic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced cellular proliferation and survival in the gastric epithelium. Furthermore, bone marrow chimeras revealed that TLR2-expressing immune/inflammatory cells are dispensable for gastric tumorigenesis. Consistent with our mouse data, in human gastric cancer (epithelial) cells we identified that TLR2 is a direct transcriptional target of STAT3, and activating TLR2 using synthetic lipopeptides promoted cell proliferation via multiple TLR signaling cascades. In human gastric cancer, both increased STAT3 pathway activation and TLR2 expression were negatively associated with patient survival. Conclusion Normally considered an innate immunepathogen recognition receptor, our data reveals an unexpected role for TLR2 in gastric tumorigenesis, whereby increased STAT3 activation results in over-expression of TLR2 to promote gastric epithelial cell growth.