Aldehyde dehydrogenase^high gastric cancer stem cells are resistant to chemotherapy

Cancer stem cells (CSCs) are known to influence chemoresistance, survival, relapse and metastasis. Aldehyde dehydrogenase (ALDH) functions as an epithelial CSC marker. In the present study, we investigated the involvement of ALDH in gastric CSC maintenance, chemoresistance and survival. Following screening for eight candidate markers (CD13, CD26, CD44, CD90, CD117, CD133, EpCAM and ALDH), five gastric cancer cell lines were found to contain small subpopulations of high ALDH activity (ALDH^high cells). We also examined the involvement of ALDH^high cell populations in human primary tumor samples. Immunodeficient NOD/SCID mice were inoculated with tumor tissues obtained from surgical specimens. ALDH^high cells were found to persist in the xenotransplanted primary tumor samples. In the immunodeficient mice, ALDH ^high cells exhibited a greater sphere-forming ability in vitro and tumorigenic potential in vivo, compared with subpopulations of low ALDH activity (ALDH^low c e l l s). Cell cultures treated with 5-fluoro uracil and cisplatin exhibited higher numbers of ALDH^high cells. Notch1 and Sonic hedgehog (Shh) expression was also found to increase in ALDH ^high cells compared with ALDH^low cells. Therefore, it can be concluded that ALDH generates chemoresistance in gastric cancer cells through Notch1 and Shh signaling, suggesting novel treatment ta rgets.