In a so-called Correa's cascade, chronic gastric inflammation predisposes atrophic gastritis and IM. Now it is established that the most important cause of chronic gastritis is Helicobacter pylori (H. pylori) infection. However, the precise molecular mechanisms leading to IM had been unknown. To elucidate the mechanisms, we focused our research on the homeobox transcriptional factors, CDX1 and CDX2, which were reported to be critical in conferring intestinal phenotype (Fig. 1). In humans, two homologous CDX1 and CDX2 are known, and CDX1 had been reported to be ectopically expressed in the Barrett's esophagus and IM, but the role of CDX2 was not known. Thus, we examined the temporal and topological expression pattern of both CDX1 and CDX2 in patients with chronic gastritis in conjunction of intestinal marker gene expressions and found that the expression of CDX2, but not CDX1, occurred early in the mucosa without intestinal gene expression. CDX1 expression was observed later in the mucosa expressing intestinal marker genes. Therefore, we suspect that ectopic expression of CDX2 in the inflammatory gastric mucosa might trigger the molecular events leading to IM. To support this hypothesis, we generated CDX2-transgenic mice by expressing a transgene construct containing H+,K+-ATPase promoter attached to CDX2 gene to guide its expression in the parietal cells. About one month after birth, foci of intestinal metaplastic glands emerged in the corpus mucosa which spread to the entire corpus mucosa by 6 months after birth. In another mice model of IM using Foxa3 promoter construct, however, the IM observed was limited in the antrum and dissimilar to the human IM in terms of structural organization and was not extensive as shown in a patchy absorptive cells, indicating the importance of the selected promoter that could influence the ectopic expression of CDX2 in a particular cell type. A detailed analysis of the sequence of molecular signature expressions in our CDX2-transgenic mice verified that CDX2 expression emerged before apparent expression of intestinal marker genes that shape intestinal phenotype, whereas CDX1 expression was observed concurrently with intestinal gene expressions. In this mouse model of IM, pseudopyloric metaplasia (spasmolytic polypeptide-expressing metaplasia: SPEM) remained in the bottom of the metaplastic glands, indicating a hybrid nature of the gland architecture. Although CDX1-transgenic mice also showed IM, but the IM were not widespread and no cancerous lesions were observed. Therefore, CDX2 seemed to be more important in inducing IM. Indeed, CDX2 can activate endogenous CDX1 gene expression. Importantly, cancerous lesions developed in the IM in almost all the mice when kept for 2 years (Fig. 2). This process was shortened when CDX2-transgenic mice were crossed with p53 deficient mice or APC (adenomatous polyposis coli) mutant Min mice. These experimental data indicate that IM may be a direct precursor of gastric cancer, but there are controversies that the majority of intestinal type of human gastric cancers develops from so-called gastric-intestinal mixed glands. However, the gastric-intestinal mixed glands have principally been defined by mucin histochemistry. As described above, CDX2 gene expression occurs before such phenotypic changes (including mucin expression),[6, 8] and therefore CDX2 was also expressed in the so-called gastric-intestinal mixed glands. Conversely, SOX2 [(Sex determining region Y)-related high-mobility-group (HMG) box transcription factor 2 more simply known as SRY/HMG box 2 transcriptional factor] gene expression whose expression is limited in the normal stomach was simultaneously observed not only in our mice model, but also in human IM (Fig. 3). Thus, apparent intestinal glands showed mixed expression in terms of transcriptional factors SOX2 and CDX2 whose expressions in the normal condition are limited to the stomach and intestine, respectively. As proposed by McDonald and colleagues, multiple stem cells may exist in a single gastric unit, and it may take a long time to have an entire gastric unit replaced by progenies from a single stem cell. Therefore, classification of gastric-intestinal mixed gland and intestinal gland based on expression of gastric mucins (MAC5Ac, MAC6) and intestinal mucin (MAC2), respectively seems to be too simplistic. It would be more reasonable to assume that IM is a hybrid state where multiple progenitors are changing their cell fates in a differential manner. In support of this hypothesis, microRNA (miRNA) expression profile of the IM in the CDX2-transgenic mice was more closely related to the original gastric mucosa than intestinal mucosa (unpublished observation). Thus, IM may be better defined that it is not a true trans-differentiation but a “disguised state” of gastric cells, as miRNA expression profile can be more informative in elucidating the developmental lineage.