Conversion of mouse neural stem cells into glioma cancer stem cells

Gliomas are the most common and lethal primary adult human brain cancers. The most lethal form of glioma is glioblastoma multiforme (GBM). Multiple apparently differentiated cell types are present within these tumours, including varying proportions of astrocytes and oligodendrocytes. The identification of new GBM subtypes, the role of the cell-of-origin and the role of commonly disrupted genes are active areas of investigation. Of particular interest to this laboratory is the recent realisation that GBMs may be driven by and initiated from tumorigenic stem cells. Our goal was to develop a mouse model of the disease based on genetic manipulation of in vitro neural stem (NS) cell lines. Importantly, this would enable us to define the contribution of each oncogenic pathway in altering the self-renewal of these cells. The original hypothesis was that the simultaneous activation of three critical pathways (RTK/PI3K, Rb and p53) would be required to confer a glioma-like phenotype. However, surprisingly we found that forced expression of the commonly amplified cyclin dependent kinase-4 (CDK4) was sufficient to elicit reduced dependency on growth factor signalling and a decreased sensitivity to the differentiation factor BMP4. Moreover, preliminary results indicate that the mRNA expression of the proto-oncogene Akt2 increases in CDK4 transfectants, suggestive of a feedback mechanism. We tested whether constitutive expression of Akt2 together with CDK4 increases the severity of the phenotype and initial results suggest this is the case. These findings provide encouragement that minimal genetic events will be required in order to transform NS cells in vitro. These cells can now be tested for in vivo tumorigenicity following transplantation. Finally, we have also generated CDK4 overexpressing cell lines in a specific NS cell variant which I identified as expressing an oligodendrocyte differentiation bias (MG1-7). We are therefore now in a position to assess whether differentiation behaviour is affected by the disruption of this pathway. Together these findings highlight the utility of mouse NS cells as a tool to study glioma

Radtke, Freddy
Austin Smith laboratory, Wellcome trust centre for stem cell research (cscr), University of Cambridge, UK

 Record created 2009-12-08, last modified 2018-01-28

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