Article
Molecular and phenotypic analysis of glioblastoma-derived stem cell-enriched cultures: emergence of distinct subgroups
Die molekulare und phenotypische Analyse von Tumorstammzellen aus menschlichen Glioblastomen zeigt die Existenz verschiedener Untergruppen von Tumorstammzellen
Search Medline for
Authors
Published: | May 30, 2008 |
---|
Outline
Text
Objective: The cancer stem cell hypothesis proposes that tumors contain a small subset of cells with stem cell-like properties, which have the exclusive ability to self-renew and sustain the growth of glioblastoma. Reports that glioblastoma stem cells are resistant to conventional radiation and chemotherapy have been taken to suggest that development of more effective therapies for glial malignancies would be facilitated by the existence of in vitro and in vivo models that faithfully recapitulate the stem cell component of these lesions.
Methods: We generated cell lines from glioblastoma specimens with the goal to obtain model systems for glioma stem cell biology. Long-term cultures of glioblastoma-derived stem cell-enriched cultures were extensively characterized using immunohistochemistry, Real time-PCR, FACS analysis and differentiation- and self-renewal assays. Gene expression analysis of glioblastoma stem-like cell cultures were performed using Affymetrix HG-U133 Plus 2.0 chips. Tumorigenicity and in vivo growth characteristics were analyzed after intracerebral implantation in nude mice.
Results: Unsupervised analysis of the expression profiles of nine cell lines established under neural stem cell conditions yielded two distinct clusters. Four cell lines were characterized by the expression of neurodevelopmental genes. They showed a multipotent differentiation profile along neuronal, astroglial and oligodendroglial lineages, grew spherically in vitro, expressed CD133 and formed highly invasive tumors in vivo. The other five cell lines shared expression signatures enriched for extracellular matrix-related genes, had a more restricted differentiation capacity, contained no or fewer CD133 cells, grew semiadherent or adherent in vitro and displayed reduced tumorigenicity and invasion in vivo.
Conclusions: Our findings show that stable, multipotent glioblastoma cell lines with a full stem-like phenotype express neurodevelopmental genes as a distinctive feature, which may offer therapeutic targeting opportunities. The generation of another distinct cluster of cell lines showing similarly homogeneous profiling but restricted stem cell properties suggests that different phenotypes exist, each of which may lead to the typical appearance of glioblastoma.