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Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APCMin/+ mice

Oncogene volume 33, pages 369–377 (2014)Cite this article

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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 APCMin/+ mice (CD4-TLR4-APCMin/+), a model of colorectal carcinoma, resulted in a dramatic drop in tumor load as compared with control APCMin/+ mice. Intestinal tumors from CD4-TLR4-APCMin/+ 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.

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Acknowledgements

Our research work was funded by a grant from Singapore Immunology Network (SIgN)—SIgN 10-038. We would like to thank Dr Robert Wallin for his great expertise and assistance in using the deconvolution microscope for anti-CD4 fluorescence imaging. We thank Velmurugesan Arulampalam for valuable discussions regarding our study. We also thank Arlaine Anne Bautista Amoyo, Jieshun Wong and Annika Samuelsson for their technical support with animal care and handling.

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Authors and Affiliations

  1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden

    Y Li, L Meijer & S Pettersson

  2. Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore

    Y Li

  3. National Cancer Centre, Singapore

    W L Teo, M J Low, S Pettersson & G Greicius

  4. Digestive Diseases Clinical Academic Unit, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, UK

    I Sanderson

  5. School of Biological Sciences, Nanyang Technological University, Singapore

    S Pettersson

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  1. Y Li
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Correspondence to S Pettersson.

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Li, Y., Teo, W., Low, M. et al. Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APCMin/+ mice. Oncogene 33, 369–377 (2014). https://doi.org/10.1038/onc.2012.581

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  • DOI: https://doi.org/10.1038/onc.2012.581

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