A cell-intrinsic role for TLR2–MYD88 in intestinal and breast epithelia and oncogenesis

Abstract

It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

“…Consistent with these findings, it has been shown that TLR2 signaling in cancer cells plays a tumor-promoting role through the enhancement of stemness (23,24). Moreover, the epithelial cell-specific deletion of Myd88 was observed to suppress intestinal tumorigenesis in Apc Min mice (16). These results suggest that the TLR2/CD14 signaling in "epithelial cells" promotes tumor development through the maintenance of the undifferentiated status of tumor cells.…”

“…On the other hand, the NF-kB pathway is activated in both differentiated (tubular type and papillary type) and undifferentiated (mucinous type) human gastric cancers, which suggests that the MyD88/NF-kB pathway is Table S2). The expression of Tlr2 and Cd14 in intestinal and mammary epithelial cells is associated with the activation of Wnt signaling, which may explain the increased stemness and tumorigenicity (16). We herein showed that Wnt/b-catenin signaling is significantly suppressed and that differentiation is induced in gastric tumors by Myd88 disruption, supporting the idea that TLR2/CD14 signaling enhances the stemness of tumor cells through activation of Wnt signaling.…”

“…Importantly, we show that MyD88 signaling in BMDCs is required for the generation of the inflammatory microenvironment in tumors even though the COX-2/PGE 2 pathway is activated. Moreover, inflammatory responses induce the expression of TLR2 and CD14 in tumor epithelial cells, which have been shown to play tumor-promoting roles through enhancement of stem cell properties (16,23,24). These results indicate that both the MyD88 signaling and the COX-2/PGE 2 pathway are required for generation of the inflammatory microenvironment, which may promote tumorigenesis through the induction of TLR2/ CD14 signaling in tumor cells.…”

“…Mouse genetics studies have indicated that signaling through myeloid differentiation factor 88 (MyD88), which is an effector molecule of the TLRs, is required for the development of sporadic intestinal tumors (14)(15)(16), colitis-associated colon cancer (17,18), gastric cancer (19), liver cancer (20), skin tumors, and sarcomas (21).…”

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

“…In accordance, Tlr2 and Tlr4 were found to regulate the proliferation of intestinal stem cells and of Lgr5 expression, even though the effects were reported to be mediated either by the adapter Trif 28 or MyD88. 29 Of note, expression of MyD88 in myeloid cells was sufficient to induce expression of the transcription factor Slug , a master-induced of epithelia-mesenchymal transition, indicating that signaling factors released by macrophages induce EMT.…”