Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
Cancer Sci. 2010 Mar;101(3):673-8. doi: 10.1111/j.1349-7006.2009.01430.x. Epub 2009 Dec 18.
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.
与正常组织干细胞类似，癌症干细胞（CSC）被认为处于静止或缓慢循环状态，因此对化疗和放疗不敏感。细胞表面成分 CD44 与细胞外基质相互作用，已被发现高度表达于几种实体瘤的 CSC 中。然而，CD44(+)细胞与慢循环细胞之间的相关性，以及在肿瘤发生过程中 CD44(+)CSC 出现的潜在机制尚未阐明。在这里，我们显示正常小鼠胃的鳞柱状交界处（SCJ）处的胃腺含有 CD44(+)干细胞样慢循环细胞，并且这种特征性的 CD44(+)腺在前列腺素 E2（PGE2）和 Wnt 信号的作用下在 K19-Wnt1/C2mE 小鼠中得到扩展，K19-Wnt1/C2mE 是一种用于胃肿瘤发生的遗传小鼠模型。对三个转基因小鼠系，K19-Wnt1、K19-C2mE 和 K19-Wnt1/C2mE 的分析表明，CD44(+)SCJ 细胞的扩增是由 PGE2 介导的信号触发的，并且 Wnt 激活的加入显著增强了这种扩增。此外，在 K19-Wnt1/C2mE 小鼠的胃肿瘤中，每个扩增的 CD44(+)腺都包含少数 BrdU 标记保留的静止或慢循环细胞，这表明正常小鼠的 CD44(+)SCJ 细胞是胃 CSC 的起源细胞候选者。这些观察结果表明，PGE2 介导的炎症信号和 Wnt 信号协同触发 SCJ 中 CD44(+)慢循环干细胞样细胞的扩增，导致小鼠致命性胃肿瘤的发展。
