Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor

PLoS One. 2008 May 7;3(5):e2090. doi: 10.1371/journal.pone.0002090.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / analysis
  • Antigens, CD / immunology*
  • Apoptosis / radiation effects
  • Cell Cycle / radiation effects
  • Child
  • Child, Preschool
  • DNA Repair / genetics
  • Embryonal Carcinoma Stem Cells
  • Female
  • Glycoproteins / analysis
  • Glycoproteins / immunology*
  • Humans
  • Infant
  • Male
  • Mice
  • Mice, SCID
  • Neoplastic Stem Cells / immunology
  • Peptides / analysis
  • Peptides / immunology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Small Interfering
  • Radiation Tolerance*
  • Radiation, Ionizing
  • Rhabdoid Tumor / diagnosis*
  • Rhabdoid Tumor / immunology
  • Rhabdoid Tumor / pathology


  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering