CD44+ slow‐cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis

(Cancer Sci 2010; 101: 673–678) Similar to normal tissue stem cells, cancer stem cells (CSCs) are thought to be quiescent or slow‐cycling and, thereby, insensitive to chemo‐ and radiotherapies. CD44, a cell surface component that interacts with the extracellular matrix, has been found to be highly expressed in CSCs of several solid tumors. However, the relevancy between CD44+ cells and slow‐cycling cells and the underlying mechanisms for the emergence of CD44+ CSCs during tumorigenesis have not been elucidated. Here we show that a gastric gland residing at the squamo‐columnar junction (SCJ) in normal mouse stomach contains CD44+ stem cell‐like slow‐cycling cells and that this characteristic CD44+ gland was expanded by prostaglandin E2 (PGE2) and Wnt signaling in K19‐Wnt1/C2mE mouse, a genetic mouse model for gastric tumorigenesis. The analysis of three transgenic mouse lines, K19‐Wnt1, K19‐C2mE and K19‐Wnt1/C2mE, revealed that the expansion of CD44+ SCJ cells is triggered by PGE2‐mediated signaling and is prominently enhanced by the addition of Wnt activation. Furthermore, each expanded CD44+ gland in gastric tumor of K19‐Wnt1/C2mE mouse contains a few BrdU label‐retaining quiescent or slow‐cycling cells, suggesting that the CD44+ SCJ cells in normal mouse are candidates for the cell‐of‐origin of gastric CSCs. These observations suggest that PGE2‐mediated inflammatory signaling and Wnt signaling cooperatively trigger the expansion of CD44+ slow‐cycling stem‐like cells in SCJ, leading to development of lethal gastric tumors in mice.