New Roles for TLR2 Gastric Cancers Are Often Associated TLR2 Has a Role in Gas- with Inflammation

RESEARCH HIGHLIGHTS

SIGNALLING New roles for TLR2 Gastric cancers are often associated TLR2 has a role in gas- with inflammation. As a result, the tric tumorigenesis. They activation of Toll-like receptors found that the incidence (TLRs) — which are receptors for and mass of gastric tumours microbial antigens in the innate and were significantly reduced adaptive immune responses — have in gp130F/F Tlr2–/– mice even been implicated in the pathogenesis though STAT3 activation and of these types of cancer; so, Brendan IL-11 expression were both upregu- Jenkins and colleagues investigated lated at comparable levels to those in this connection further. gp130F/F tumours. Surprisingly, his- The gp130F/F knock-in mouse tological and immunohistochemical model spontaneously develops analyses of gp130F/F Tlr2–/– tumours intestinal-type gastric tumours at 6 revealed that immune cell infiltrates weeks of age that are driven by were comparable to those of gp130F/F interleukin-11 (IL-11)–signal trans- tumours, indicating that the inflam- ducer and activator of transcription 3 matory reaction in gastric tumori (STAT3) signalling. Gene expression genesis was unaffected by profiling of tumours from these mice Tlr2 ablation. revealed that Tlr2 levels were signifi- If TLR2 is not cantly increased and that this was driving immune cell Neil Smith dependent on IL-11 signalling infiltration of gastric and STAT3 activation. Hyperactivated tumours, what is it doing? The gastric and the suppression of apoptosis that STAT3, upregulated IL-11 signalling epithelium of gp130F/F Tlr2–/– mice were induced on TLR2 activation. and increased TLR2 expression were had a reduced proliferation zone Finally, treating gp130F/F mice bear- also observed in a second transgenic compared with gp130F/F mice, ing established gastric tumours (at 12 mouse model of gastric cancer and and the surface epithelium was weeks of age) with a TLR2-blocking in samples of human gastric cancer, proliferating cell nuclear antigen antibody, OPN-301, twice weekly for indicating that these factors are (PCNA)-negative and had markers 10 weeks substantially reduced the important in gastric tumorigenesis. of apoptosis, whereas gp130F/F surface size, number and overall burden of Furthermore, patients with STAT3hi epithelium did not. Furthermore, gastric tumours. indicating TLR2hi gastric tumours had reduced human gastric cancer cell lines Tye et al. have characterized a that the overall survival in comparison to treated with TLR2 ligands increased non-inflammatory role of TLR2 inflammatory those with STAT3lo TLR2lo tumours. proliferation in a dose-dependent signalling in gastric epithelia that What is the connection between manner. This proliferation was promotes survival and proliferation reaction STAT3 and TLR2? Chromatin abrogated by treating these cells and suppresses apoptosis; therefore, in gastric immunoprecipitation experiments with inhibitors of PI3K–AKT, ERK, targeting TLR2 could be an avenue tumorigenesis showed that IL-11-treated gastric JUN N-terminal kinase (JNK) or for treating STAT3hi IL-11hi gastric was unaffected epithelial cells or tumour tissue from nuclear factor-κB (NF-κB) signalling tumours. gp130F/F mice had phosphorylated pathways, which are activated by Gemma K. Alderton by Tlr2 F/F STAT3 bound to the Tlr2 promoter, TLR2. Consistently, treating gp130 ORIGINAL RESEARCH PAPER Tye, H. et al. ablation and further experiments showed that mice with a MEK inhibitor, U0126, STAT3-driven upregulation of TLR2 promotes TLR2 is a target gene of STAT3. Next, suppressed the expression of genes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22, 466–478 (2012) the authors investigated whether associated with survival, proliferation

NATURE REVIEWS | CANCER VOLUME 12 | DECEMBER 2012