The development of gastric cancer is inextricably linked with inflammation, dictated by deregulation of the innate immune system. However, the intrinsic molecular events leading to the tumorigenesis of gastric epithelial cells in the context of aberrant inflammatory signaling is poorly understood.
We have recently identified that Toll-like receptor (TLR)2 is critical for promoting the development of gastric cancer. Utilising a large patient cohort, we determined that ~40% of gastric cancer patients with advanced disease have significantly enhanced expression of the Toll-like receptor (TLR)2, and that TLR2 expression is significantly associated with reduced survival in these patients. Moreover, genetic ablation of TLR2 in a gp130F/F genetic mouse model of gastric cancer resulted in a significant reduction in disease incidence and severity. Upon further investigation, we have found that TLR2 signaling induces a pro-proliferative and anti-apoptotic cascade in human gastric epithelial cells, promoting tumour development independent of inflammation.
We are currently investigating the contribution of both host- and pathogen-derived TLR2 ligands to the induction of gastric cancer, and are beginning to reveal the molecular mechanisms by which TLR2 signaling is required for gastric cancer development. This work will ultimately lead to the elucidation of a TLR2-associated molecular signature of gastric cancer, significantly enhancing both biomarker discovery and novel therapeutic development in order to improve the poor outcomes currently observed in patients with gastric cancer.