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

Abstract

It has been established that COX-2 and downstream signaling by prostaglandin E 2 (PGE 2 ) play a key role in tumorigenesis through generation of inflammatory microenvironment. Tolllike receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE 2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE 2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE 2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE 2 pathway will be an effective preventive strategy for gastric cancer.Cancer Prev Res; 9(3); 253-63. Ó2016 AACR.

Inflammation in gastric cancer: Interplay of the COX‐2/prostaglandin E2 and Toll‐like receptor/MyD88 pathways

“…Innate immune responses through the TLRs have also been shown to be involved in tumor promotion . We have shown that the COX‐2/PGE 2 pathway triggers generation of inflammatory microenvironment in the stomach in a mouse gastric tumor model, and that TLR signaling through the adaptor molecule MyD88 is required for COX‐2/PGE 2 ‐induced gastritis and gastric tumor development . Accordingly, it is possible that the interplay of the COX‐2/PGE 2 and TLR/MyD88 pathways is important for generation of the inflammatory microenvironment, which promotes tumorigenesis.…”

A single transcription factor is sufficient to induce and maintain secretory cell architecture

“…Mice were maintained on a mixed background. Tamoxifen (Sigma-Aldrich) was injected intraperitoneally in mice using both "high-dose" and "low-dose" protocols that have been extensively vetted previously by our laboratory and others (Huh et al , 2012Capoccia et al 2013;Khurana et al 2013;Maeda et al 2016;Saenz et al 2016). Doses of 5 mg per 20 g of mouse body weight ("high-dose") delivered on three consecutive days cause the death of >90% of PCs within 4 d of the initial dose followed by recovery to a full complement of PCs by 3 wk.…”

From inflammation to gastric cancer: Role of Helicobacter pylori

“…2) (30). Besides these, innate immune responses through the TLR/MyD88 adapter signaling also play a role in tumorigenesis (31,32). In fact, it has been shown that almost all the gastric tumors show an induction of COX-2 expression (33) and H. pylori infection is known to lead to COX-2 induction (34).…”