Editors' ChoiceCancer

The Noninflammatory Side of TLR2

Science Signaling  13 Nov 2012:
Vol. 5, Issue 250, pp. ec289
DOI: 10.1126/scisignal.2003772

Microbes are detected by Toll-like receptors (TLRs), and inflammation caused by microbial infection is a risk factor for the development of gastric cancer. Polymorphisms in TLR2 and TLR4 are associated with increased risk for developing gastric cancer. Tye et al. investigated the role of TLR2 in gastric cancer using gp130F/F mice, which spontaneously develop gastric tumors and are a model for human gastric cancer because they share some phenotypic characteristics, such as increased activation of the transcription factor STAT3 and production of interleukin (IL)–11. In human gastric tumors, increased activation of STAT3 positively correlated with increased expression of TLR2, and the combination of increased STAT3 activation and TLR2 expression correlated with decreased overall survival. Chromatin immunoprecipitation assays performed on IL-11–treated gastric epithelial cells or gp130F/F tumor tissue revealed that tyrosine-phosphorylated and active STAT3 was recruited to the TLR2 promoter, indicating that TLR2 was a target gene for STAT3. gp130F/F mice lacking TLR2 (gp130F/F:Tlr2–/–) had smaller stomachs, smaller gastric tumors, and fewer gastric lesions compared with control mice (gp130F/F) or gp130F/F mice lacking TLR4 (gp130F/F:Tlr4–/–). Although transcriptional profiling of gp130F/F mice revealed increased expression of TLR2-regulated genes encoding proinflammatory factors, histological examination indicated no difference between gp130F/F and gp130F/F:Tlr2–/– mice in the infiltration of and activation of immune cells in gastric epithelium. Instead, gp130F/F:Tlr2–/– mice showed reduced proliferation and increased apoptosis in gastric epithelia compared with gp130F/F mice, a phenotype that required signaling through the nuclear factor κB (NF-κB), the phosphoinositide 3-kinase (PI3K) Akt, and the mitogen-activated protein kinase pathways mediated by ERK1 and 2 and JNK, but not by p38. Injection of a TLR2-blocking antibody into gp130F/F mice reduced stomach size and tumor burden. These results suggest the potential of TLR2 as a therapeutic target in gastric cancer.

H. Tye, C. L. Kennedy, M. Najdovska, L. McLeod, W. McCormack, N. Hughes, A. Dev, W. Sievert, C. H. Ooi, T.-o. Ishikawa, H. Oshima, P. S. Bhathal, A. E. Parker, M. Oshima, P. Tan, B. J. Jenkins, STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22, 466–478 (2012). [PubMed]