Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression

Abstract

Toll-like receptor (TLR) stimulation results in activation of NF-κB, a key modulator in driving inflammation to cancer and mitogen-activated protein kinases that have been shown to recruit mitotic and cyclooxygenase-2 (COX-2) induced pathways in carcinogenesis. Here we asked whether different TLR, COX-2 and stem cell marker expression profiles in colorectal cancer (CRC) provide further evidence for this hypothesis from a clinical perspective. We analysed gene and protein expression of TLR7-TLR10, COX-2 and CD133 as a marker for colon-initiating cells in CRC patients ( n = 65). Gene analysis demonstrated significantly upregulated TLR7–TLR10 and COX-2 expression in CRC tumour tissues. Analysis of isolated tumour cells from primary tumours showed co-expression of TLR7 and TLR8 with CD133 and gave evidence for a subpopulation of colon cancer-initiating cells. In multivariate analyses TLR8 expression was found to be an independent prognostic factor. Persistent TLR-specific activation of NF-κB in CRC and particularly in tumour-initiating cells may thus sustain further tumour growth and progression through perpetuated signalling known from inflammatory and tissue repair mechanisms with consecutive self-renewal in pluripotent tumour cells. Activation through self-ligands or viral RNA fragments may putatively maintain this inflammatory process, suggesting a key role in cancer progression.