Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

3.2 Brain Cancer Stem Cells Introduction
The study by Bao et al [40] aimed at assessing the resistance of the CD133 +
cells to ionization therapies caused by the more efficient and active DNA re-
pair mechanisms present in these cells with respect to the rest constituting the
bulk of the tumour. The observations in this study showed that after ionizing-
radiation treatment of glioblastoma cells grown in vitro or as grafts in mice,
the surviving fraction was enriched in CD133 + cells. These cells had the ability
to reinitiate heterogeneous tumours when transplanted into other mice, thus
demonstrating retention of their stem cell abilities. To assess the biological
relevance of the enriched CD133 + cells, xenografts with a constant number of
total cells but increasing fraction of CD133 + cells were generated that showed
a dose-dependent decrease in tumour latency, enhancement of tumour growth
and vascularity. The successive irradiation of these xenografts demonstrated
that viable tumour cells enriched for CD133 + cells could form secondary tu-
mours with decreased latencies themselves, demonstrating that enrichment of
CD133 + cells is crucial in glioma recurrence after radiotherapy. The CD133 +
tumour cells showed characteristics consistent with cancer stem cells, i.e. neu-
rosphere formation, expression of neural and cancer stem cell markers CD133,
Sox2, Musashi and Nestin, as well as multi-lineage differentiation with mark-
ers for astrocytes, neurons or oligodendrocytes. Furthermore, CD133 + cells
derived from xenografts or biopsy specimens formed neurospheres, whereas
CD133 - cells rarely did. Finally, CD133 + tumour cells were highly tumouri-
genic in brains of immunocompromised mice with characteristics of glioblas-
toma and CD133 - cells did not form detectable tumours even when implanted
with high doses of CD133 - cells, showing that CD133 + subpopulations were
enriched for characteristics of cancer stem cells, including tumourigenesis in
vivo [40].
Although ionizing radiation damages tumour cells through several mechanisms,
it kills cancer cells primarily through DNA damage, identifying DNA damage
checkpoint responses as having essential roles in cellular radio-sensitivity [40].
Progression through the mitotic cycle is driven by cyclin-CDK complexes,
which ensure that all phases of the cell cycle are executed in the correct order.
Terminally differentiated neurons cannot undergo cell cycle re-entry and CDK
activity is suppressed through interactions with two main families of inhibitory
proteins, the INK4 family that exhibits selectivity for CDK4 and CDK6, and
the CIP/KIP family that has a broader range of CDK inhibitory activity (Fig
3.3) [115]. As demonstrated in the study by Bao et al, activating phosphoryla-
tion of the checkpoint proteins Ataxia telangiectasia mutated (ATM), RAD17,
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