Gastric-to-intestinal transdifferentiation and cancer.

I n The Curious Case of Benjamin Button, an original short story authored by F. Scott Fitzgerald, the main character ages in reverse, beginning life as a mature adult (i.e., welldifferentiated state) and then progressing inexorably toward a childlike existence (i.e., progenitor state). A molecular counterpart to this process, which frequently occurs during oncogenesis, is transdifferentiation, in which cells transition from a welldifferentiated state to a progenitor state, which is then followed by the reemergence of a different cell lineage (i.e., metaplasia). Intestinal-type gastric cancer epitomizes this process during its progression from normal mucosa, to chronic gastritis and atrophy, to intestinal metaplasia, and finally to dysplasia and adenocarcinoma. The annual incidence of gastric cancer is estimated to be 0.1% for patients with atrophy but increases 2.5 fold for patients with intestinal metaplasia, underscoring the premalignant potential of this lesion (1). In PNAS, Fujii et al. provide fresh insights into the molecular underpinnings that regulate the development of intestinal metaplasia within the stomach (2). The strongest known risk factor for intestinal-type gastric adenocarcinoma is chronic colonization by the bacterial pathogen Helicobacter pylori (3). However, only a percentage of colonized cases show the development of neoplasia, and enhanced risk is related to H. pylori strain differences, host responses governed by genetic diversity, and/or specific interactions among host, microbial, and environmental determinants (4). One H. pylori strain-specific virulence locus that augments cancer risk is the cag pathogenicity island, which encodes a type IV secretion system (TFSS) that functions as a molecular syringe to inject microbial proteins into host cells. The product of the cagA gene (CagA) is translocated by the TFSS into epithelial cells and undergoes targeted tyrosine phosphorylation by Src and Abl kinases at motifs (termed A, B, C, or D) containing the amino acid sequence EPIYA (5–7). Phospho-CagA activates a cellular phosphatase (SHP-2) and ERK MAPK, leading to morphological aberrations that mirror changes induced by growth factor stimulation (8, 9). However, nonphosphorylated CagA also exerts effects with carcinogenic potential, including activation of β-catenin (10), which can occur via PI3-kinase– dependent inhibition of GSK-3β (11). Previously, Murata-Kamiya et al. identified another mechanism through which CagA can activate β-catenin in gastric epithelial cells: physical interaction with E-cadherin and disruption of the E-cadherin–β-catenin complex, leading to β-catenin translocation from the membrane into the nucleus (12) (Fig. 1). Of interest in that study, the authors noted that CagAderegulated β-catenin transactivated the intestinal specific transcription factor CDX1, which was followed by up-regulation of the intestinal differentiation marker Muc2 (12), findings that provided the framework for the work of Fujii et al. (2). Fujii et al. (2) begin with a manipulatable gastric epithelial cell system, Tet-Off