title: CD44+ slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis.
abstract: 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 (PGE(2)) 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 PGE(2)-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 PGE(2)-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.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Kai
authors.forename: Ryota
authors.initials: R
authors.lastname: Torii
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000502:physiology; D015232:Dinoprostone / Q000502:physiology*; D005260:Female; D018960:Hyaluronan Receptors / Q000032:analysis / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D000071876:Prostaglandin-E Synthases; D051381:Rats; D011916:Rats, Inbred F344; D013274:Stomach Neoplasms / Q000209:etiology*; D051155:Wnt1 Protein / Q000502:physiology*
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone