0000000000024032
AUTHOR
Apostolos Polykratis
Innate Sensing by Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis
MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis, which is dependent on its function in the stroma. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces Apc-mediated intestinal tumorigenesis. 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 IL1R, in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis…
Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis.
The mechanisms that regulate cell death and inflammation play an important role in liver disease and cancer. Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF…
Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis
Summary 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 …