title: Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis.
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.
authors.affiliation: Department of Pathology & Laboratory Medicine, Radiation Oncology, and Neurosurgery, Winship Cancer Institute, Emory University School Medicine, 1365-C Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.forename: Anita C
authors.initials: AC
authors.lastname: Bellail
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Pang
authors.forename: Stephen
authors.initials: S
authors.lastname: Hunter
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cohen
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Shibo
authors.initials: S
authors.lastname: Li
authors.forename: Chunhai
authors.initials: C
authors.lastname: Hao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002889:Chromosomes, Human, Pair 2 / Q000737:chemistry / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D005819:Genetic Markers; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D005819:Genetic Markers; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8