MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization

The signal adaptor MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. Far less is known about the specific effects of MyD88 signaling in myofibroblasts in CAC development. Here, we used a CAC mouse model in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient mice are resistant to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumorigenesis, as evidenced by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts attenuates intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increases the secretion of osteopontin (OPN), which promotes macrophage M2 polarization through binding to alpha(v)beta(3) and CD44, leading to activation of the STAT3/PPARg pathway. Thus, MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis.

Automated summary

The signal adaptor MyD88 plays a crucial role in colorectal cancer development, particularly in myofibroblasts. MyD88-deficient mice show resistance to drug-induced tumorigenesis, indicating the importance of MyD88 signaling in cancer development.