Medulloblastoma-derived tumor stem-like cells acquired resistance to TRAIL-induced apoptosis and radiosensitivity.
OBJECTIVE
Medulloblastoma (MB) is the most malignant primary brain tumor in early childhood that contains cellular and functional heterogeneity. Recent evidence has demonstrated that the tumor stem cells (TSC) may explain the radiochemoresistance of brain tumors, including MB. The aim of the present study is to investigate the possible role of TNF-related apoptosis-inducing ligand (TRAIL) in viability and tumorigenicity of MB cells and MB-derived TSC.


METHODS
MB-associated TSC were isolated and cultured by serum-free medium with bFGF and EGF. The parental MB cells and MB-TSC cells were treated with TRAIL in different concentrations and assessed for cell viability, invasion ability, colony forming ability, and radiotherapy effect.


RESULTS
We enrich a subpopulation of MB-TSC cells using tumor spheroid formation approach. MB-TSC display enhanced self-renewal and highly expressed "stemness" genes (CD133, Sox-2, Bmi1, Nestin). Additionally, MB-TSC showed significant resistance to TRAIL-induced apoptosis and radiosensitivity compared to the parental MB cells due antiapoptotic gene (c-FLIP, Caspase 8, Bcl-2, and Bax) upregulation.


CONCLUSIONS
Our data suggest that MB-TSC are resistant to TRAIL-induced apoptosis and tumorigenic properties. Understanding the molecular mechanisms by which to operate the physiological characteristics in MB-TSC cells offers attractive approach for MB treatment.
Yu
Cheng-Chia
CC
Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Chiou
Guang-Yuh
GY
Lee
Yi-Yen
YY
Chang
Yuh-Lih
YL
Huang
Pin-I
PI
Cheng
Yi-Wei
YW
Tai
Lung-Kuo
LK
Ku
Hung-Hai
HH
Chiou
Shih-Hwa
SH
Wong
Tai-Tong
TT
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D003124:Colorimetry; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand