Gastroenterology

Gastroenterology

Volume 131, Issue 4, October 2006, Pages 1086-1095
Gastroenterology

Basic–alimentary tract
Carcinogenesis in Mouse Stomach by Simultaneous Activation of the Wnt Signaling and Prostaglandin E2 Pathway

https://doi.org/10.1053/j.gastro.2006.07.014Get rights and content

Background & Aims: Accumulating evidence indicates that prostaglandin E2 (PGE2), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. The Wnt pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Wnt and PGE2 pathways contribute to gastric tumorigenesis. To investigate the role of Wnt and PGE2 in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes. Methods: We constructed K19-Wnt1 transgenic mice expressing Wnt1 in the gastric mucosa using the keratin 19 promoter. We then crossed K19-Wnt1 mice with another transgenic line, K19-C2mE, to obtain K19-Wnt1/C2mE compound transgenic mice. The K19-C2mE mice express COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach, showing an increased gastric PGE2 level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice. Results: K19-Wnt1 mice had a significant suppression of epithelial differentiation and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. Importantly, additional expression of COX-2 and mPGES-1 converted the preneoplastic lesions in the K19-Wnt1 mice into dysplastic gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development. Conclusions: Wnt signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Wnt and PGE2 pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence.

Section snippets

Tissue Samples

In total, 80 patients were preoperatively diagnosed with sporadic gastric cancer (47 intestinal type and 33 diffuse type) in 1998–1999 at Kanazawa University Hospital, Japan. Any patients with signet ring cell carcinoma were excluded because of the difficulty in evaluating nuclear β-catenin staining. All experiments were carried out according to the protocol approved by the Ethics Committee of Kanazawa University. Informed consent was obtained from all participants.

Transgenic Mice

The K19 promoter with a

Activation of the Wnt Pathway in Human Gastric Cancer Tissues

We first examined 80 cases of gastric cancer (47 and 33 cases for the intestinal type and diffuse type, respectively) by immunohistochemistry (Figure 1). The nuclear localization of β-catenin was detected in 24 and 19 cases of intestinal-type and diffuse-type gastric cancer, respectively, whereas β-catenin was found in the basolateral membrane of the adjacent normal tissues of the same patients (Figure 1B, C, E and F). These results suggest that the Wnt pathway is activated in 54% of the

Discussion

Wnt signaling plays an important role in the maintenance of the intestinal crypt containing the stem cells and undifferentiated progenitor cells.14, 15 In the gastric gland, Wnt signaling also keeps the progenitor cells undifferentiated in the isthmus of the gastric gland because we have shown that the number of progenitors increased significantly in the K19-Wnt1 mouse stomach. It has been reported that Wnt signal activation was found in 30% of the human gastric cancer examined.4 In the present

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      In line with the findings above are those obtained in the K19-Wnt1/C2mE (also called Gan) mouse model of gastric carcinogenesis [41]. These transgenic animals express Wnt1, COX-2, and PGE2 in the gastric mucosa, and develop gastric tumours with histological features resembling those of the human intestinal-type gastric cancer [42]. Gan mice raised under GF conditions develop significantly smaller tumours than SPF-Gan mice.

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    Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H.O., M.M.T. and M.O.) and the Uehara Memorial Foundation (to H.O.).

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