Abstract
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-cateninSer552, 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.
Highlights
Colorectal cancer (CRC) is the second and third most common type of cancer in women and men, respectively, and accounts for more than half of the cancer diagnoses in developed countries [1]
We showed that toll-like receptor 4 (TLR4) knock-out mice are protected against CAC [9], whereas mice over-expressing TLR4 in the intestinal epithelium are prone to developing inflammatory neoplasia [7]
We examined tissue arrays composed of adenomas and sporadic CRCs for TLR4 expression by immunofluorescent staining (Figure 1a)
Summary
Colorectal cancer (CRC) is the second and third most common type of cancer in women and men, respectively, and accounts for more than half of the cancer diagnoses in developed countries [1]. We have previously identified a link between toll-like receptor signaling in inflammatory bowel disease (IBD) and colitisassociated cancer (CAC) [7]. Our studies showed that the majority of dysplasia and cancers occurring in the setting of IBD demonstrate over-expression of toll-like receptor 4 (TLR4)–the receptor for lipopolysaccharide (LPS) from Gram-negative bacteria [7]. There is a certain rate of bacterial translocation and exposure to LPS on the basolateral side of the epithelium, especially during epithelial injury, which may turn on inflammatory responses through TLR4 signaling [8]. We showed that TLR4 knock-out mice are protected against CAC [9], whereas mice over-expressing TLR4 in the intestinal epithelium are prone to developing inflammatory neoplasia [7]
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