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

Shih Hwa Chiou, Chung Lan Kao, Yi Wei Chen, Chien Shu Chien, Shih Chieh Hung, Jeng Fan Lo, Yann Jang Chen, Hung Hai Ku, Ming Ta Hsu, Tai-Tong Wong

Research output: Contribution to journalArticle

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Abstract

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-radiated CD133+ xenografts 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.

Original languageEnglish
Article numbere2090
JournalPLoS One
Volume3
Issue number5
DOIs
Publication statusPublished - May 7 2008
Externally publishedYes

Fingerprint

Ionizing radiation
Ionizing Radiation
ionizing radiation
Tumors
neoplasms
Automatic teller machines
cells
Neoplastic Stem Cells
Microarrays
Tissue
Radiation Dosage
Germ Layers
Central Nervous System Neoplasms
Phosphorylation
cisplatin
stems
SCID Mice
Typical Teratoid Rhabdoid Tumor
Atypical Teratoid Tumor
mice

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor. / Chiou, Shih Hwa; Kao, Chung Lan; Chen, Yi Wei; Chien, Chien Shu; Hung, Shih Chieh; Lo, Jeng Fan; Chen, Yann Jang; Ku, Hung Hai; Hsu, Ming Ta; Wong, Tai-Tong.

In: PLoS One, Vol. 3, No. 5, e2090, 07.05.2008.

Research output: Contribution to journalArticle

Chiou, SH, Kao, CL, Chen, YW, Chien, CS, Hung, SC, Lo, JF, Chen, YJ, Ku, HH, Hsu, MT & Wong, T-T 2008, 'Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor', PLoS One, vol. 3, no. 5, e2090. https://doi.org/10.1371/journal.pone.0002090
Chiou, Shih Hwa ; Kao, Chung Lan ; Chen, Yi Wei ; Chien, Chien Shu ; Hung, Shih Chieh ; Lo, Jeng Fan ; Chen, Yann Jang ; Ku, Hung Hai ; Hsu, Ming Ta ; Wong, Tai-Tong. / Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor. In: PLoS One. 2008 ; Vol. 3, No. 5.
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abstract = "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-radiated CD133+ xenografts 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.",
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AU - Hung, Shih Chieh

AU - Lo, Jeng Fan

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AU - Wong, Tai-Tong

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