New roles for TLR2

Credit: Neil Smith

Gastric cancers are often associated with inflammation. As a result, the activation of Toll-like receptors (TLRs) — which are receptors for microbial antigens in the innate and adaptive immune responses — have been implicated in the pathogenesis of these types of cancer; so, Brendan Jenkins and colleagues investigated this connection further.

The gp130^F/F knock-in mouse model spontaneously develops intestinal-type gastric tumours at 6 weeks of age that are driven by interleukin-11 (IL-11)–signal transducer and activator of transcription 3 (STAT3) signalling. Gene expression profiling of tumours from these mice revealed that Tlr2 levels were significantly increased and that this was dependent on IL-11 signalling and STAT3 activation. Hyperactivated STAT3, upregulated IL-11 signalling and increased TLR2 expression were also observed in a second transgenic mouse model of gastric cancer and in samples of human gastric cancer, indicating that these factors are important in gastric tumorigenesis. Furthermore, patients with STAT3^hi TLR2^hi gastric tumours had reduced overall survival in comparison to those with STAT3^lo TLR2^lo tumours.

indicating that the inflammatory reaction in gastric tumorigenesis was unaffected by Tlr2 ablation

What is the connection between STAT3 and TLR2? Chromatin immunoprecipitation experiments showed that IL-11-treated gastric epithelial cells or tumour tissue from gp130^F/F mice had phosphorylated STAT3 bound to the Tlr2 promoter, and further experiments showed that TLR2 is a target gene of STAT3. Next, the authors investigated whether TLR2 has a role in gastric tumorigenesis. They found that the incidence and mass of gastric tumours were significantly reduced in gp130^F/FTlr2^−/− mice even though STAT3 activation and IL-11 expression were both upregulated at comparable levels to those in gp130^F/F tumours. Surprisingly, histological and immunohistochemical analyses of gp130^F/FTlr2^−/− tumours revealed that immune cell infiltrates were comparable to those of gp130^F/F tumours, indicating that the inflammatory reaction in gastric tumorigenesis was unaffected by Tlr2 ablation.

If TLR2 is not driving immune cell infiltration of gastric tumours, what is it doing? The gastric epithelium of gp130^F/FTlr2^−/− mice had a reduced proliferation zone compared with gp130^F/F mice, and the surface epithelium was proliferating cell nuclear antigen (PCNA)-negative and had markers of apoptosis, whereas gp130^F/F surface epithelium did not. Furthermore, human gastric cancer cell lines treated with TLR2 ligands increased proliferation in a dose-dependent manner. This proliferation was abrogated by treating these cells with inhibitors of PI3K–AKT, ERK, JUN N-terminal kinase (JNK) or nuclear factor-κB (NF-κB) signalling pathways, which are activated by TLR2. Consistently, treating gp130^F/F mice with a MEK inhibitor, U0126, suppressed the expression of genes associated with survival, proliferation and the suppression of apoptosis that were induced on TLR2 activation. Finally, treating gp130^F/F mice bearing established gastric tumours (at 12 weeks of age) with a TLR2-blocking antibody, OPN-301, twice weekly for 10 weeks substantially reduced the size, number and overall burden of gastric tumours.

Tye et al. have characterized a non-inflammatory role of TLR2 signalling in gastric epithelia that promotes survival and proliferation and suppresses apoptosis; therefore, targeting TLR2 could be an avenue for treating STAT3^hi IL-11^hi gastric tumours.