Connecting brain tumor stem cells with their primary tumor and exploring glycogen synthase kinase -3ß regulation of cell fate
Malignant brain tumors such as gliomas can arise from a subpopulation of cells frequently called glioma stem cells (GSCs). These cells are often resistant to conventional therapies, hence are the likely culprits of tumor recurrence. Here, we describe the derivation of a human GSC line, NNI-8. Our method preserves the karyotypic integrity of the primary tumor, and our xenograft recapitulates the original patient histopathology. Furthermore, a stem cell signature derived from NNI-8 could stratify patients for survival in a clinical database. This infers that GSCs contribute to disease outcome and survival. In a small molecule screen targeting GSCs, we identified glycogen synthase kinase 3-beta (GSK3ß) inhibitors as likely candidates. We observed that pharmacological and genetic knockdown of GSK3 induced apoptosis and differentiation, preferentially in the CD133-expressing tumor-initiating fraction. In addition, GSC frequency was significantly reduced. Our data suggest that targeting GSK3 presents a viable treatment strategy in eradicating self-renewing GSCs.
brain tumor, stem cells, GSK3ß, CD133, apoptosis, differentiation
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