title: Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice.
abstract: The microbial pattern-recognizing Toll-like receptors (TLRs) are major signal transducers known to shape and influence the postnatal maturation of host intestinal epithelium. Perturbations in this intricate host-microbe cross-talk have been reported to be associated with uncontrolled epithelial cell growth and thus potential cancer development by mechanisms which are largely unknown. We therefore generated transgenic mice carrying a constitutively active TLR4 (CD4-TLR4) linked to an intestinal epithelial cell-specific promoter. Ex vivo analysis of transgenic crypt-villus organoid cultures revealed an increased proliferative capacity and a lowered cyclooxygenase 2 (Cox-2) expression in these organoids compared with wild-type control cultures. Introducing the CD4-TLR4 transgene into APC(Min/+) mice (CD4-TLR4-APC(Min/+)), a model of colorectal carcinoma, resulted in a dramatic drop in tumor load as compared with control APC(Min/+) mice. Intestinal tumors from CD4-TLR4-APC(Min/+) mice displayed reduced Cox-2 protein, elevated interferon β expression and increased caspase-3 activity, which correlated with increased apoptosis in vivo. Thus, our data reveal that host microbiota-mediated signal transduction via TLR4 in intestinal epithelial cells is far more complex than what is previously reported.
authors: 1] Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden [2] Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore.
authors: Y
authors: Y
authors: Li
authors: National Cancer Centre, Singapore.
authors: W L
authors: WL
authors: Teo
authors: National Cancer Centre, Singapore.
authors: M J
authors: MJ
authors: Low
authors: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden.
authors: L
authors: L
authors: Meijer
authors: Digestive Diseases Clinical Academic Unit, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, UK.
authors: I
authors: I
authors: Sanderson
authors: 1] Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden [2] National Cancer Centre, Singapore [3] School of Biological Sciences, Nanyang Technological University, Singapore.
authors: S
authors: S
authors: Pettersson
authors: National Cancer Centre, Singapore.
authors: G
authors: G
authors: Greicius
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D051546:Cyclooxygenase 2; D053148:Caspase 3