To clarify the mechanism of the development of gastric well differentiated carcinoma from intestinal metaplasia

在慢性胃炎的发展过程中，胃粘膜细胞偏离正常的胃分化途径，转变为肠道表型。胃肠化生是胃粘膜的一种病理状态。肠特异性转录因子CDX2在人胃肠化生黏膜中表达。我们建立了在胃粘膜表达转录因子CDX2的转基因小鼠。Cdx2转基因小鼠的胃底粘膜完全转化为肠化生黏膜，许多流行病学研究发现肠化生的形成与胃癌的发生有关。然而，到目前为止，还没有直接证据表明肠化生是胃癌的前驱病变。我们定期检测了转基因小鼠的肠化生黏膜。在研究的所有转基因小鼠的胃中，胃息肉都是从肠化生黏膜发展而来的。这些胃息肉由肠型腺癌组成，侵犯粘膜下层和固有肌层，偶尔扩散到浆膜下。腺癌中存在P53和APC基因突变。携带APC和P53基因突变或P53缺失的转基因小鼠比单独携带Cdx2基因的小鼠更早发生胃息肉，证实了APC和P53基因突变参与了肠化生引起的胃癌的发生。我们成功地证明了长期肠上皮化生可诱发浸润性胃癌。这些结果表明，肠化生本身在胃癌的发生和发展中起着重要作用。

In the progression of chronic gastritis, gastric inucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype. Gastric intestinal metaplasia occurs as a pathological condition in the gastric mucosa. The intestine-specific transcription factor Cdx2 is expressed in the human gastric intestinal metaplastic mucosa. We established Cdx2-transgenic mice expressing transcription factor Cdx2 in the gastric mucosa. The gastric fundic mucosa of the Cdx2-transgenic mice was completely changed into intestinal metaplastic mucosa.Many epidemiological studies have found an association between the formation of intestinal metaplasia and the development of gastric carcinoma. However, there is no direct evidence which shows intestinal metaplasia is a precursor lesion of gastric carcinoma to date. We periodically examined the intestinal metaplastic mucosa of Cdx2-transgenic mice. Gastric polyps developed from intestinal metaplastic mucosa in all stomachs of Cdx2-transgenic mice examined. These gastric polyps consisted of intestinal-type adenocarcinoma that invaded the submucosa and muscularis propria, and occasionally spread into the subserosa. p53 and APC gene mutations were recognized in the adenocarcinomas. The participation of APC and p53 gene mutations in gastric carcinogenesis from the intestinal metaplasia was verified by the Cdx2-transgenic mice, carrying Apc^<Min> mutation or p53 deficiency, that developed gastric polyps much earlier than Cdx2 alone. We successfully demonstrated that long-term intestinal metaplasia induces invasive gastric carcinoma. These results indicate that intestinal metaplasia itself plays a significant role in the genesis and progression of gastric carcinoma.