title: Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy.
abstract: 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.
authors: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors: Shimpei
authors: S
authors: Nishikawa
authors: Masamitsu
authors: M
authors: Konno
authors: Atsushi
authors: A
authors: Hamabe
authors: Shinichiro
authors: S
authors: Hasegawa
authors: Yoshihiro
authors: Y
authors: Kano
authors: Katsuya
authors: K
authors: Ohta
authors: Takahito
authors: T
authors: Fukusumi
authors: Daisuke
authors: D
authors: Sakai
authors: Toshihiro
authors: T
authors: Kudo
authors: Naotsugu
authors: N
authors: Haraguchi
authors: Taroh
authors: T
authors: Satoh
authors: Shuji
authors: S
authors: Takiguchi
authors: Masaki
authors: M
authors: Mori
authors: Yuichiro
authors: Y
authors: Doki
authors: Hideshi
authors: H
authors: Ishii
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D053823:Hedgehog Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C509239:SHH protein, human; D000444:Aldehyde Dehydrogenase; D002945:Cisplatin; D005472:Fluorouracil