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. (Cancer Sci 2010; 101: 673-678) C D44, a major cell adhesion molecule, has been implicated in a wide variety of physiological processes and pathological processes, including lymphocyte homing, wound healing, and cell migration, as well as cancer cell growth and metastasis.(1,2) CD44 has been recently detected as a cell surface marker of cancer stem cells (CSCs) in several types of cancer.(3) Moreover, a CD44 + subpopulation of cells isolated from several gastric cancer cell lines has been reported to have stem cell-like properties, which are the capacities to self-renew and to differentiate.(4) However, the underlying mechanism by which CD44 + CSC-like subpopulations emerge in the process of tumor development is largely unknown. Cancer stem cells, also known as cancer-initiating cells, are responsible for tumor initiation and maintenance. CSCs possess the ability to drive tumor growth and are inherently resistant to chemo-and radiotherapies. Recent studies have revealed that melanoma-initiating cells (5) and leukemia-initiating cells are a slow-cycling or quiescent subpopulation.(6,7) These quiescent or slow-cycling properties are thought to be a major reason why CSCs are resistant to cancer therapies targeted at proliferating cells. It has been shown that cell adhesion molecules play an essential role in the quiescence of hematopoietic stem cells by regulating adhesion in the osteoblastic niche.(8) Therefore, we hypothesized that CD44, which is highly expressed in CSCs, is involved in the regul...

shRNA against CD44 inhibits cell proliferation, invasion and migration, and promotes apoptosis of colon carcinoma cells

“…β-catenin is a downstream molecule in the Wnt signaling pathway and plays important roles in the structural organization and function of cell-to-cell adhesion and tumor invasion and metastasis (42). CD44 can also regulate Wnt-target genes (43). Among them, Akt is important for the survival of cancer cells (21).…”

TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells

“…26,27 Because CD44 is a marker of normal and cancer stem cells, 28 we examined CD44 expression and differentiation status of epithelial cells in Tnf À / À Gan mouse tumors. In the Tnf þ / þ or Tnf þ / À Gan mouse tumors, CD44 mRNA levels increased significantly, by more than eightfold, the Figure 3a).…”

Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells

“…Against this background, we evaluated whether Mcl-1 knockdown was effective for sensitizing chemotherapy-induced apoptosis in CSC-like populations in gastric cancer cells. We used a cell surface marker molecule, CD44, which is reported to be a CSC marker in gastric cancer [12][13][14][15][16][17], to identify chemotherapy-resistant subpopulations. We found that the Mcl-1 expression level was relatively high in CD44-positive gastric cancer cells.…”