Colonic bacteria have been implicated in the development of
colon cancer. We have previously demonstrated that
toll-like receptor 4 (TLR4), the receptor for bacterial
lipopolysaccharide (LPS), is over-expressed in humans with
colitis-associated cancer. Genetic epidemiologic data support a role for TLR4 in sporadic
colorectal cancer (CRC) as well, with over-expression favoring more aggressive disease. The goal of our study was to determine whether TLR4 played a role as a
tumor promoter in sporadic
colon cancer. Using immunofluorescence directed to TLR4, we found that a third of sporadic human
colorectal cancers over-express this marker. To mechanistically investigate this observation, we used a mouse model that over-expresses TLR4 in the intestinal epithelium (villin-TLR4 mice). We found that these transgenic mice had increased epithelial proliferation as measured by
BrdU labeling, longer colonic crypts and an expansion of Lgr5+ crypt cells at baseline. In addition, villin-TLR4 mice developed spontaneous duodenal dysplasia with age, a feature that is not seen in any wild-type (WT) mice. To model human sporadic CRC, we administered the genotoxic agent
azoxymethane (AOM) to villin-TLR4 and WT mice. We found that villin-TLR4 mice showed an increased number of colonic
tumors compared to WT mice as well as increased β-
catenin activation in non-dysplastic areas. Biochemical studies in colonic epithelial cell lines revealed that TLR4 activates β-
catenin in a PI3K-dependent manner, increasing phosphorylation of β-catenin(Ser552), a phenomenon associated with activation of the canonical Wnt pathway. Our results suggest that TLR4 can trigger a neoplastic program through activation of the Wnt/β-
catenin pathway. Our studies highlight a previously unexplored link between innate immune signaling and activation of oncogenic pathways, which may be targeted to prevent or treat CRC.