Open AccessCD44 + slow‐cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E 2 in gastric tumorigenesis
Author(s) -
Ishimoto Takatsugu,
Oshima Hiroko,
Oshima Masanobu,
Kai Kazuharu,
Torii Ryota,
Masuko Takashi,
Baba Hideo,
Saya Hideyuki,
Nagano Osamu
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01430.x
Subject(s) - cd44 , wnt signaling pathway , carcinogenesis , cancer stem cell , stem cell , biology , cancer research , microbiology and biotechnology , cell , signal transduction , cancer , biochemistry , genetics
( 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 (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.