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Author Notes:

Correspondence: Chunhai Hao, Department of Pathology & Laboratory Medicine, Radiation Oncology, and Neurosurgery, Winship Cancer Institute, Emory University School Medicine, 1365-C Clifton Road, Atlanta, Georgia 30322, USA; Email: chao@emory.edu

Author Contributions: Ling Qi and Anita C. Bellail contributed equally to this study.

Acknowledgements: We thank Diane Lawson for her technical support.

Disclosures: C.H. was a Georgia Cancer Coalition Distinguished Scholar.

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Research Funding:

This work was supported by National Institutes of Health grant CA129687 (C. H.) and Southeastern Brain Tumor Foundation research award (C.H.).

Keywords:

  • Apoptosis
  • cancer stem cells
  • caspase-8
  • glioblastoma
  • TRAIL

Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis

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Journal Title:

Apoptosis

Volume:

Volume 16, Number 11

Publisher:

, Pages 1150-1164

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Recent studies suggest that cancer stem cells (CSCs) are responsible for cancer resistance to therapies. We therefore investigated how glioblastoma-derived CSCs respond to the treatment of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Neurospheres were generated from glioblastomas, characterized for CSC properties including self-renewal, cell differentiation and xenograft formation capacity, and analyzed for TRAIL-induced apoptosis, CASP8 genomic status, and caspase-8 protein expression. The neurosphere NSC326 was sensitive to TRAIL-induced apoptosis as evidenced by cell death and caspase-8, -3, and -7 enzymatic activities. In contrast, however, the neurosphere NSC189 was TRAIL-resistant. G-banding analysis identified five chromosomally distinguishable cell populations in the neurospheres. Fluorescence in situ hybridization revealed the variation of chromosome 2 copy number in these populations and the loss of CASP8 locus in 2q33-34 region in a small set of cell populations in the neurosphere. Immunohistochemistry of NSC189 cell blocks revealed the lack of caspase-8 protein in a subset of neurosphere cells. Western blotting and immunohistochemistry of human glioblastoma tumors demonstrated the expression of caspase-8 protein in the vast majority of the tumors as compared to normal human brain tissues that lack the caspase-8 expression. This study shows heterogeneity of glioblastomas and derived CSCs in the genomic status of CASP8, expression of caspase-8, and thus responsiveness to TRAIL-induced apoptosis. Clinic trials may consider genomic analysis of the cancer tissue to identify the genomic loss of CASP8 and use it as a genomic marker to predict the resistance of glioblastomas to TRAIL apoptosis pathway-targeted therapies.

Copyright information:

© Springer Science+Business Media, LLC 2011

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