Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models

Abstract

The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori-associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE(2). The COX-2/PGE(2) pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/beta-catenin signaling is found in 30-50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE(2) pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt-activated and BMP-suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE(2), Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE(2) induction, Wnt activation, BMP suppression, or a combination of these pathways.

Figure 1

Schematic presentation of arachidonic acid metabolism in the context of gastric tumorigenesis. The expression of cyclooxygenase (COX)‐2 and microsomal PGE synthase‐1 (mPGES‐1) is induced by Helicobacter pylori (H. pylori)‐associated inflammatory responses. The simultaneous expression of both COX‐2 and mPGES‐1 leads to induction of the prostaglandin PGE₂ pathway, which results in macrophage accumulation. These macrophages are activated by infectious stimuli, resulting in the induction of tumor necrosis factor (TNF)‐α‐dependent SPEM development and the promotion of Wnt signaling, which may contribute to gastric tumorigenesis. The induction of angiogenesis and activation of epidermal growth factor receptor (EGFR) signaling are also possible mechanisms of PGE₂ in tumorigenesis. COXIBs, COX‐2 selective inhibitors; NF‐κB, nuclear factor‐κB; NSAIDS, nonsteroidal anti‐inflammatory drugs; SPEM, spasmolytic polypeptide/TFF2‐expressing metaplasia; TLRs, Toll‐like receptors.

Figure 2

Transgenic mouse models of gastric tumorigenesis. Transgenic vector construction(s) and representative macroscopic and microscopic photographs of the stomach are shown for each line. K19‐Wnt1/C2mE and K19‐Nog/C2mE are compound transgenic mice of K19‐Wnt1 and K19‐C2mE, and K19‐Nog and K19‐C2mE, respectively. The arrowhead in the K19‐Wnt1 mouse stomach indicates a preneoplastic lesion. The arrowheads and asterisks in the K19‐C2mE mouse stomach indicate gastric hyperplasia and mucous metaplasia (SPEM), respectively. The arrows in K19‐Wnt1/C2mE and K19‐Nog/C2mE indicate gastric tumors. Note that the histology of the K19‐Wnt1/C2mE mouse shows dysplastic adenocarcinoma, while that of the K19‐Nog/C2mE mouse shows hamartoma with dilated cystic structure. Bars indicate 100 µm. (Reproduced from Oshima et al. Cancer Res, 69: 2729–33, 2009.) BMP, bone morphogenetic protein; COX‐2, cyclooxygenase‐2; SPEM, spasmolytic polypeptide/TFF2‐expressing metaplasia.

Figure 3

Schematic presentation of the canonical Wnt signaling and cyclooxygenase (COX)‐2/prostaglandin PGE₂ pathway in gastric tumor development. β‐Catenin mutations, SFRPs methylation, and downregulation of E‐cadherin or β‐TrCP can activate Wnt signaling in gastric cancer. Cooperation of the Helicobacter pylori (H. pylori)‐induced COX‐2/PGE₂ pathway with Wnt activation leads to the development of gastric adenocarcinoma. Without the induction of the PGE₂ pathway, Wnt activation alone does not cause gastric cancer development. mPGES‐1, microsomal PGE synthase‐1.

Figure 4

Promotion of Wnt signaling by macrophage‐derived tumor necrosis factor (TNF)‐α in gastric cancer cells. (a) Representative FACS analyses of Wnt‐reporter gastric cancer cells, AGS‐GFP, in which GFP expression is regulated by β‐catenin/TCF. GFP intensity increased significantly when cells were treated with conditioned medium (CM) from activated macrophages. (b) GFP intensity of reporter cells treated with indicated cytokines are shown in the bar graph. Note that Wnt activity is elevated by treatment with TNF‐α in a dose‐dependent manner. (c) Hypothesis for gastric tumor development. The level of Wnt signaling activated by genetic/epigenetic alteration is not sufficient for tumorigenesis. However, Helicobacter pylori (H. pylori) infection‐induced inflammation promotes the Wnt activation level through macrophage‐derived TNF‐α, which contributes to gastric tumorigenesis. (a and b, reproduced from Oguma et al. EMBO J, 27: 1671–81, 2008, with permission from the Nature Publishing Group.)