In silico and Ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer

Background: Inflammation increases the risk of colorectal cancer (CRC). We and others have described a role for TLR4, the receptor for LPS, in colon cancer. To explore the relationships between TLR4 expression and CRC, we combined the strength of transcriptome array data and immunohistochemical (IHC) staining. Methods: TLR4 signal intensity was scored in the stromal and epithelial compartments. Detection of differential expression between conditions of interest was performed using linear models, Cox proportional hazards models, and empirical Bayes methods. Results: A strong association between TLR4 expression and survival was noted, though a dichotomous relationship between survival and specific TLR4 transcripts was observed. Increasing TLR4 expression was seen with advancing tumor stage and was also over-expressed in some adenomas. IHC staining confirmed the positive relationship between TLR4 staining score in the CRC tumor stroma and epithelium with tumor stage, with up to 47% of colon cancer stroma positive for TLR4 staining. Increased TLR4 expression by IHC was also marginally associated with decreased survival. We now also describe that pericryptal myofibroblasts are responsible for a portion of the TLR4 stromal staining. Conclusions: Increased TLR4 expression occurs early in colonic neoplasia. TLR4 is associated with the important cancer-related outcomes of survival and stage.