Toll-like Receptor 2 Promotes STAT3-Driven Gastric Tumorigenesis

Chronic inflammation has been linked to the pathogenesis of multiple tumor types, including gastric cancer. These tumors frequently exhibit hyperactivation of the oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3), which stimulates cancer cell growth and promotes a protumorigenic inflammatory microenvironment. Tye and colleagues used a mouse model of STAT3-driven gastric tumorigenesis to investigate the potential cross-talk between STAT3 and Toll-like receptor 2 (TLR2), an innate immune receptor that has also been implicated in inflammatory-related epithelial cancers. Tlr2 expression was increased in murine gastric tumors and correlated with STAT3 activation; elevated TLR2 expression was also observed in human gastric tumor samples and was associated with reduced overall survival in patients with gastric cancer. This increase was directly mediated by STAT3-dependent transcriptional upregulation of Tlr2 in gastric epithelial cells. Ablation of Tlr2 significantly diminished gastric tumor incidence and size, indicating that TLR2 functions downstream of STAT3 to promote gastric tumorigenesis. However, Tlr2 deficiency did not affect the composition or activation status of gastric inflammatory cell infiltrates, and reconstitution of Tlr2 in bone marrow–derived inflammatory cells did not enhance tumor formation, suggesting a tumor cell–intrinsic function for TLR2. Indeed, Tlr2 deficiency resulted in impaired proliferation and enhanced apoptosis of tumor epithelial cells, whereas stimulation of TLR2 signaling induced the expression of multiple genes involved in cell-cycle regulation and inhibition of apoptosis, supporting the idea that TLR2 promotes the growth and survival of gastric epithelial cells independent of tumor inflammation. Strikingly, treatment with a TLR2-blocking antibody significantly diminished gastric tumor burden in this mouse model. These results identify TLR2 as an important mediator of the oncogenic effects of STAT3 in epithelial cells and suggest TLR2 inhibition as a potential therapeutic strategy for patients with gastric cancer.

Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 2012;22:466–78.