Compelling evidence has demonstrated that the bulk of tumor cells is generated by a rare population of self-renewing, multipotent cells with the ability to initiate and sustain tumor growth, commonly termed cancer stem cells (CSCs). Several cancers have been shown to arise from such tumor-initiating cells: Leukemia, cancers of the breast, brain, colon, prostate. Glioblastoma multiforme (GBM) is the most common and deadly of primary adult brain tumors. Our lab explores the role of brain tumor stem cells in adult malignant brain tumors.
Our Findings
We and others have shown that tumor neurospheres (mixture of stem and progenitor cells) isolated from GBM tumor tissue contain genotypic and karyotypic hallmarks of GBM; importantly, these cells are able to reform xenografts in immune-compromised mice that recapitulate glioma pathophysiology. We have defined the existence of at least 2 genetic subtypes of GBM tumor spheres. Our free-floating tumor spheres are upregulated in “stemness” genes while the semi-adherent tumor spheres express gene signatures typically found in glioma tissue specimens. These 2 genetically distinct subtypes of GBM tumor-initiating cells; however, yield the same morphology of tumor tissue; this is significant as current treatment regimens are decided based on tumor morphology. This may explain patient variability in treatment response. In addition, we have established a cryopreservation method that maintains the integrity of these tumor-initiating cells for the development of the first human brain tumor stem cell repository for future investigations.
Future Directions
Microarray gene expression analysis has uncovered differential regulation of several key signaling transduction genes between the 2 subtypes of tumor spheres. The pathways regulating brain tumor stem cell proliferation remain poorly defined, but molecular targets such as Notch, Hedgehog and Wnt/?-catenin with defined roles in normal stem cell biology have been implicated in cancers. Here, we hypothesize that different GBM subtypes may be distinguished by their response to anti-cancer therapeutics. We are currently exploring this work through compound screening with academic and pharmaceutical partners.
Address: National Neuroscience Institute 11 Jalan Tan Tock Seng S(308433)
