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Cell Rep. 2019 Jan 15;26(3):536-545.e4. doi: 10.1016/j.celrep.2018.12.072.

Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis.

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Biomedical Sciences Research Centre (BSRC) "Alexander Fleming," Vari 16672, Greece. Electronic address:
Biomedical Sciences Research Centre (BSRC) "Alexander Fleming," Vari 16672, Greece.
Institute for Genetics, University of Cologne, Cologne 50674, Germany.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany.
Faculty of Biology, Medicine and Health, University of Manchester, Manchester M139PT, UK.
Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Bloomberg Children's Center, Baltimore, MD 21287, USA.
Biomedical Sciences Research Centre (BSRC) "Alexander Fleming," Vari 16672, Greece; Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece. Electronic address:


MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apcmin/+ model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not interleukin-1 receptor (IL-1R), in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis in IMCs indicated that these effects could be mediated through downstream signals involving growth factors and inflammatory and extracellular matrix (ECM)-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and promote carcinogenesis in the intestine.


cancer-associated fibroblasts; innate immunity; tumor microenvironment

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