Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophages

Schiechl, Gabriela; Bauer, B. L.; Fuss, Ivan J.; Lang, Sven A.; Moser, Christian; Ruemmele, Petra; Rose-John, Stefan; Neurath, Markus F.; Geissler, Edward K.; Schlitt, Hans-Jürgen; Strober, Warren; Fichtner‐Feigl, Stefan

doi:10.1172/jci42540

Cited by 81 publications

(69 citation statements)

References 56 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, MyD88 signaling induces the expression of COX-2 and inflammatory cytokines in tumor tissues, which contribute to the inflammatory microenvironment generation (14,17,18,20). However, relationship between the COX-2/PGE 2 pathway and TLR/MyD88 signaling in the induction of inflammatory responses and the promotion of tumorigenesis is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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

Maeda

Echizen

Oshima

et al. 2016

Cancer Prevention Research

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Maeda

Echizen

Oshima

et al. 2016

Cancer Prevention Research

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“…Chronic oxazolone-induced colitis begins as severe inflammation with corresponding weight loss, which transforms into chronic inflammation and partial weight recovery. The inflammation is marked by the rapid increase in the production of IL13 in the lamina propria and the appearance of NK T cells, which are both immunologic features of acute oxazolone-induced colitis (69). The authors also concluded that the chronic oxazoloneinduced colitis model supports epithelial tumour development induced by administration of a carcinogenic agent, azoxymethane.…”

Section: Induction Of Oxazolone Colitismentioning

confidence: 95%

“…Over the next 3 weeks the surviving mice regained weight and no longer exhibited obvious signs of chronic illness. Repetitive administration of intra-rectal ethanol alone led to a weight loss of up to 5% in the early phase of the disease (68).…”

Section: Features Of Oxazolone-induced Colitismentioning

confidence: 99%

“…More recently, oxazolone-induced colitis has been established as a chronic model via repeated intrarectal administration of oxazolone in ethanol. This allows the model to be used to define specific features of the inflammatory milieu that favors tumor development (69). Chronic oxazolone-induced colitis begins as severe inflammation with corresponding weight loss, which transforms into chronic inflammation and partial weight recovery.…”

Section: Induction Of Oxazolone Colitismentioning

confidence: 99%

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