Abstract 914: The role of CD44 variant in the development of spasmolytic polypeptide-expressing metaplasia (SPEM) and gastric cancer

Abstract

Abstract CD44 is a marker of tumor-initiating cells in gastric cancer. However, the cause or consequence of elevated CD44 in such immature tumor cells is not known. Gastric carcinogenesis involves a transition from normal mucosa to gastritis, which then leads to metaplasia and eventually adenocarcinoma. Although the emergence of metaplasia or dysplasia is a key event of inflammation-related gastric carcinogenesis, the precise mechanism underlying the transition from normal gastric epithelium to metaplasia and cancer remains unsolved. Spasmolytic polypeptide (known as trefoil factor family 2)-expressing metaplasia (SPEM) results from a metaplastic change of gastric epithelial cells in response to chronic inflammation. Here we show that the trefoil factor family 2 (TFF2)+ metaplastic glands as well as gastric tumor glands contain CD44 variant isoform-expressing (CD44v+) cells in K19-Wnt1/C2mE mouse, a genetic mouse model for gastric tumorigenesis. Furthermore, the analysis of three transgenic mouse lines K19-Wnt1, K19-C2mE and K19-Wnt1/C2mE revealed that de novo expression of CD44v in SPEM cells is triggered by prostaglandin E2-mediated signaling. Isolated CD44-expressing tumor cells in K19-Wnt1/C2mE mice by fluorescence-activated cell sorting (FACS) manifested increased expression of SPEM-related genes, suggesting that metaplastic epithelium might give rise to both of CD44v+ tumor cells and CD44v+ SPEM cells in mice. To investigate the role of CD44 in the development of SPEM and gastric tumor in mice, we generated CD44-/- K19-Wnt1/C2mE mice. We found that CD44 ablation significantly suppresses the development of SPEM and gastric tumor, suggesting that CD44v+ cells play a key role in gastric tumorigenesis. Furthermore, we found that the emergence of CD44v+ SPEM glands adjacent to cancer is tightly associated with the CD44v-expressing gastric cancer formation in human. Our present study thus suggest that SPEM cells might be susceptible for oncogenesis due to their proliferative capacity and that CD44v+ SPEM cells are cells-of-origin for CD44v+ tumor-initiating cells in human gastric adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 914. doi:10.1158/1538-7445.AM2011-914