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Abstract
It has been established that COX-2 and downstream signaling by prostaglandin E2 (PGE2) play a key role in tumorigenesis through generation of inflammatory microenvironment. Toll-like 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/PGE2 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/PGE2 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/PGE2 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/PGE2 pathway will be an effective preventive strategy for gastric cancer.
Highlights
Gastric cancer is the second leading cause of death from malignancy worldwide [1]
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 myeloid differentiation factor 88 (MyD88) signaling and the COX-2/prostaglandin E2 (PGE2) pathway are required for generation of the inflammatory microenvironment, which may promote tumorigenesis through the induction of TLR2/ CD14 signaling in tumor cells
The expression of stem cell marker CD44 was significantly increased in AGS cells when the cells were treated with LPS conditioned medium (CM), whereas it was suppressed by knockdown of Myd88 expression in RAW264 macrophages (Fig. 4D). These results indicate that MyD88-dependent macrophage-derived factor(s) induces the TLR2/CD14 signaling pathway in cancer cells, which may promote tumorigenesis by enhancing the undifferentiated status of the tumor cells
Summary
Gastric cancer is the second leading cause of death from malignancy worldwide [1]. Helicobacter pylori (H. pylori) infection induces chronic gastritis, which is closely associated with gastric cancer [2, 3]. We previously showed that induction of COX-2/PGE2 pathway in the gastric mucosa of K19-C2mE mice by expression of Ptgs and Ptges causes inflammatory responses in the glandular stomach [6]. Wnt signaling activation in the gastric mucosa of K19-Wnt mice by expression of Wnt results in the development of limited dysplastic lesions; the simultaneous activation of Wnt signaling and COX-2/PGE2 pathway in Gan mice leads to development of inflammation-associated gastric tumors [7, 8]. These results indicate the role of COX-2/PGE2 pathway-induced inflammation in gastric tumorigenesis. In the gastric tumor stroma, proinflammatory cytokines including TNFa, IL1b, and IL11 are expressed and promote tumorigenesis through enhancement of undifferentiated status, recruiting of myeloid-derived suppressor cells and increasing tumor cell survival [9,10,11]
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