There is a link between chronic inflammation and the development of colorectal cancers (CRC). This is seen in both the increase in number of CRC in patients with inflammatory bowel disease (IBD), as well as in the severity of cancer in patients with chronic inflammation. We have found that Toll-like receptor 1 (TLR1) is an important innate receptor in regulating mucosal immune responses. The absence of TLR1 causes dysregulated immune and epithelial cell responses leading to chronic inflammation, altered commensal microbiome and activation of pathways involved in mutagenesis. Importantly, these studies also have translational application as we have found that a mutation in TLR1, which abrogates surface expression and signaling, is associated with pediatric IBD patients. Further, patients with disrupted TLR1 signaling also have a more severe disease, loss of response to anti-TNF therapy and defects in growth. The goals of the proposed work will examine how deficient TLR1 signaling impacts the commensal microbiome and intestinal epithelial cells in a model of CRC. Specifically, we will examine whether the chronic inflammation in TLR1-deficient mice alters the commensal microbiome to a tumor promoting phenotype and the impact that the altered microbiome and TLR1 signaling have on the immune system and the epithelium. The results of these studies have important consequences on the understanding of how dysregulated innate immune signaling can impact chronic inflammation and cancer progression. Further, it will provide an understanding of whether patients with disrupted TLR1 signaling are more susceptible to chronic inflammation and CRC allowing early prevention, treatment and potential therapies.
There is a link between chronic inflammation and malignancy, which is evidenced by the high incidence of colon cancer occurring in patients with inflammatory bowel disease (IBD) and the correlation between severity of inflammation and the risk of cancer. We have found that Toll-like receptor-1 (TLR1) is critical for the regulation of mucosal immunity and mutations of TLR1 are prevalent in pediatric IBD patients. The proposed research will investigate how disrupted TLR1 signaling contributes to chronic intestinal inflammation and may impact the progression to colorectal cancer (CRC).
|Okazaki, Satoshi; Loupakis, Fotios; Stintzing, Sebastian et al. (2016) Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab. Mol Cancer Ther 15:1740-5|