Toll-like receptor (TLR) 7 and TLR8 expression in CD133+ cells in colorectal cancer and role for inflammation-induced TLRs in tumorigenesis and tumor progression.

Abstract

10626 Background: Nuclear factor-kappaB (NF-κB) was identified as a key modulator in driving inflammation to cancer. Toll like receptor (TLR) stimulation results in activation of NF-κB and mitogen-activated protein kinases (MAPKs) 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. Methods: We analysed gene and protein expression of TLR7-10, COX-2, and CD133 in CRC patients (n=65). FACS and immunofluorescence staining of TLR7 and TLR8 were specifically used to detect expression in CD133+ colon cancer initiating cells. Results: Gene analysis demonstrated significantly upregulated TLR7, TLR8, TLR9, TLR10, and COX-2 expression in CRC tumor tissues. Immunofluorescence double staining and FACS analysis of isolated tumor cells from primary tumors and from a tumor cell line 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. We found significantly increased TLR7 and TLR8 expression in CD133+ colon cancer cells. Conclusions: Persistent TLR-specific activation of NF- κB in CRC and particularly in tumor initiating cells may thus sustain further tumor growth and progression through perpetuated signalling known from inflammatory and tissue repair mechanisms with consecutive self-renewal in pluripotent tumor cells. Activation through self-ligands or viral RNA fragments may putatively maintain this inflammatory process, suggesting a key role in cancer progression. No significant financial relationships to disclose.