期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 42, 期 4, 页码 1437-1442出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2013.1837
关键词
gastric cancer; cancer stem cells; chemotherapy resistance; aldehyde dehydrogenase
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Third Term Comprehensive 10-year Strategy for Cancer Control of the Ministry of Health, Labour and Welfare, Japan
- Kobayashi Cancer Research Foundation
- Princess Takamatsu Cancer Research Fund, Japan
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [25670576, 23390199, 25112708] Funding Source: KAKEN
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. ALDHhigh 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-fluorouracil 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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