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      High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

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          Abstract

          Background:

          The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC).

          Methods:

          The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed.

          Results:

          Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis ( P=0.0001, P=0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15–4.07; P=0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31–4.13; P=0.0038 and HR: 3.03; 95% CI: 1.67–5.48; P=0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27–3.99; P=0.0053 and HR: 2.97; 95% CI: 1.64–5.38; P=0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99–3.55; P=0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01–3.67; P=0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17–4.33; P=0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS.

          Conclusion:

          Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.

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          Most cited references31

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          Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis.

          Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.
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            Toll-like receptors and cancer.

            Toll-like receptors (TLRs) are a family of pattern recognition receptors that are best-known for their role in host defence from infection. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. Here we discuss how the function of TLRs may relate to these processes in the context of carcinogenesis.
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              Toll-like receptors on tumor cells facilitate evasion of immune surveillance.

              The signal pathways that trigger tumor cell escape from immune surveillance are incompletely understood. Toll-like receptors (TLRs), which activate innate and adaptive immune responses, are thought to be restricted to immune cells. We show here that TLRs, including TLR4, are expressed on tumor cells from a wide variety of tissues, suggesting that TLR activation may be an important event in tumor cell immune evasion. Activation of TLR4 signaling in tumor cells by lipopolysaccharide induces the synthesis of various soluble factors and proteins including interleukin-6, inducible nitric oxide synthase, interleukin-12, B7-H1, and B7-H2, and results in resistance of tumor cells to CTL attack. In addition, lipopolysaccharide-stimulated tumor cell supernatants inhibit both T cell proliferation and natural killer cell activity. Blockade of the TLR4 pathway by either TLR4 short interfering RNA or a cell-permeable TLR4 inhibitory peptide reverses tumor-mediated suppression of T cell proliferation and natural killer cell activity in vitro, and in vivo, delays tumor growth and thus prolongs the survival of tumor-bearing mice. These findings indicate that TLR signaling results in a cascade leading to tumor evasion from immune surveillance. These novel functions of TLRs in tumor biology suggest a new class of therapeutic targets for cancer therapy.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                09 February 2010
                02 March 2010
                02 March 2010
                : 102
                : 5
                : 908-915
                Affiliations
                [1 ]Department of Human Pathology, Institute of Health Biosciences, University of Tokushima Graduate School 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
                [2 ]Department of Legal Medicine, Kanazawa Medical University 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
                [3 ]Department of Medicine, Tsurugi Municipal Handa-Hospital, Tsurugi-cho, Mima-gun Tokushima 779-4401, Japan
                [4 ]Department of Stress Science, Institute of Health Biosciences, University of Tokushima Graduate School 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
                [5 ]Department of Medical Pharmacology, Institute of Health Biosciences, University of Tokushima Graduate School 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan
                [6 ]Division of Pathology, Tokushima University Hospital 2-50-1 Kuramoto-cho, Tokushima 770-8503, Japan
                [7 ]Department of Surgery, Institute of Health Biosciences, University of Tokushima Graduate School 3-18-15 Kuramoto-cho Tokushima 770-8503, Japan
                Author notes
                [* ]Author for correspondence: zrqian@ 123456basic.med.tokushima-u.ac.jp
                [8]

                These authors contributed equally to this work.

                Article
                6605558
                10.1038/sj.bjc.6605558
                2833250
                20145615
                167aecbe-ab12-4791-9481-9e53ab68adfb
                Copyright 2010, Cancer Research UK
                History
                : 20 November 2009
                : 06 January 2010
                : 08 January 2010
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                colorectal cancer,prognosis,tlr4,myd88
                Oncology & Radiotherapy
                colorectal cancer, prognosis, tlr4, myd88

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