Myeloid differentiation factor 88 signaling in bone marrow-derived cells promotes gastric tumorigenesis by generation of inflammatory microenvironment

Yusuke Maeda, Kanae Echizen, Hiroko Oshima, Liang Yu, Natthiya Sakulsak, Osamu Hirose, Yoichi Yamada, Tadatsugu Taniguchi, Brendan J. Jenkins, Hideyuki Saya, Masanobu Oshima

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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. 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/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.

Original languageEnglish
Pages (from-to)253-263
Number of pages11
JournalCancer Prevention Research
Volume9
Issue number3
DOIs
Publication statusPublished - 1 Mar 2016

Cite this

Maeda, Yusuke ; Echizen, Kanae ; Oshima, Hiroko ; Yu, Liang ; Sakulsak, Natthiya ; Hirose, Osamu ; Yamada, Yoichi ; Taniguchi, Tadatsugu ; Jenkins, Brendan J. ; Saya, Hideyuki ; Oshima, Masanobu. / Myeloid differentiation factor 88 signaling in bone marrow-derived cells promotes gastric tumorigenesis by generation of inflammatory microenvironment. In: Cancer Prevention Research. 2016 ; Vol. 9, No. 3. pp. 253-263.
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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. 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/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.",
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Myeloid differentiation factor 88 signaling in bone marrow-derived cells promotes gastric tumorigenesis by generation of inflammatory microenvironment. / Maeda, Yusuke; Echizen, Kanae; Oshima, Hiroko; Yu, Liang; Sakulsak, Natthiya; Hirose, Osamu; Yamada, Yoichi; Taniguchi, Tadatsugu; Jenkins, Brendan J.; Saya, Hideyuki; Oshima, Masanobu.

In: Cancer Prevention Research, Vol. 9, No. 3, 01.03.2016, p. 253-263.

Research output: Contribution to journalArticleResearchpeer-review

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