JOURNAL ARTICLE

Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy

Shimpei Nishikawa, Masamitsu Konno, Atsushi Hamabe, Shinichiro Hasegawa, Yoshihiro Kano, Katsuya Ohta, Takahito Fukusumi, Daisuke Sakai, Toshihiro Kudo, Naotsugu Haraguchi, Taroh Satoh, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Hideshi Ishii
International Journal of Oncology 2013, 42 (4): 1437-42
23440340
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) cells). 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 targets.

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