Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

Abstract

Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation and colitis-associated colon cancer (CAC). In the present study, we analyzed the impact of TLR4, the receptor for Gram-negative bacteria derived lipopolysaccharides, on intestinal inflammation and tumorigenesis in a murine model of CAC. During the inflammatory phases of CAC development, we observed a strong upregulation of Tlr4 expression in colonic tissues. Blocking of TLR4 signaling by a small-molecule-specific inhibitor during the inflammatory phases of CAC strongly diminished the development and progression of colonic tumors, which was accompanied by decreased numbers of infiltrating macrophages and reduced colonic pro-inflammatory cytokine levels compared to CAC control mice. Interestingly, inhibiting bacterial signaling by antibiotic treatment during the inflammatory phases of CAC also protected mice from severe intestinal inflammation and almost completely prevented tumor growth. Nevertheless, application of antibiotics involved rapid and severe body weight loss and might have unwanted side effects. Our results indicate that bacterial activation of TLR4 on innate immune cells in the colon triggers inflammation and promotes tumor growth. Thus, the inhibition of the TLR4 signaling during intestinal inflammation might be a novel approach to impede CAC development.

Colorectal Cancer in Ulcerative Colitis: Mechanisms, Surveillance and Chemoprevention

“…Ultimately, microbiota-driven IL-17C induces the expression of Bcl-2 and Bcl-xl in IECs to improve IECs survival and promote cancer development [ 98 ]. In line with this, TAK-242 (a small-molecule TLR4 inhibitor) strongly suppressed the development and progression of colonic tumors during DSS-induced colitis, with reduced numbers of infiltrating macrophages and colonic proinflammatory cytokine levels [ 99 ]. Moreover, for APC Min/+ MyD88 -/- mice, both mortality and tumor numbers were dramatically decreased [ 100 ].…”

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

“…They observed that by inhibiting TLR4 with an antagonist during intestinal inflammation, the development and progression of colonic tumours was significantly reduced compared to control mice [ 30 ]. They also observed a decrease in infiltration of pro-inflammatory cells and cytokines compared to control mice [ 30 ]. CPT-11 prevented tumour growth equally well in both groups.…”

Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice

“…It can modulate both innate and adaptive immune responses through multiple pathways and mechanisms [ 29 ]. Apart from being present on immune cells, it is expressed by many tumors including skin malignancies [ 9 , 10 , 11 , 12 , 13 , 16 , 17 ]. TLR4 expression has been found to be higher in cutaneous SCCs than in normal skin [ 17 ].…”

“…Toll-like receptors are not only expressed on the cells of the immune system but are also expressed on tumor cells, where they may influence tumor growth and host immune [ 8 ]. Depending on the tumor type and/or the initiating agent, TLR4 ligation in the tumor microenvironment may have the beneficial effect of activating anti-tumor responses or the deleterious action of promoting non-specific inflammatory responses [ 9 , 10 , 11 , 12 , 13 ]. Polymorphisms in the TLR4 allele in humans have been linked to the cancer susceptibility and resistance, depending on the type of cancer studied.…”