Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor.
Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133(+)), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133(+) were significantly augmented when compared to CD133(-). The clinical data showed that the amount of CD133(+) in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic-response profiles of CD133(+) and CD133(-) irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133(+) compared to CD133(-). Furthermore, we found that CD133(+) can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133(+) xenotransgrafts in SCID mice but not in IR-treated CD133(-). Importantly, the effect of IR in CD133(+) transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133(+) AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133(+) may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133(+) could be possible targets to improve future treatment of deadly diseases like AT/RT.
Department of Medical Research and Education, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan. shchiou@vghtpe.gov.tw
Shih-Hwa
SH
Chiou
Chung-Lan
CL
Kao
Yi-Wei
YW
Chen
Chien-Shu
CS
Chien
Shih-Chieh
SC
Hung
Jeng-Fan
JF
Lo
Yann-Jang
YJ
Chen
Hung-Hai
HH
Ku
Ming-Ta
MT
Hsu
Tai-Tong
TT
Wong
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair / Q000235:genetics; D054278:Embryonal Carcinoma Stem Cells; D005260:Female; D006023:Glycoproteins / Q000032:analysis / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology; D010455:Peptides / Q000032:analysis / Q000276:immunology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D018335:Rhabdoid Tumor / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering