Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

3.2 Brain Cancer Stem Cells Introduction
ing a pro-differentiation action predominantly in the astroglial direction and
depleting the pool of tumour-initiating cells. Based on these results, it was
inferred that the in vitro reduction in the stem-cell-like tumour-initiating cells
would correspond to a similar decline in the ability of BMP4-treated cells to
form tumours in vivo. By transiently exposing glioblastoma cells to BMP4,
in fact, the tumour-initiating stem-like population produced a significant de-
crease in the in vivo tumour-initiating ability of glioblastoma cells, since it
effectively blocked the tumour growth and associated mortality in 100% of the
mice subjected to intracerebral grafting. It is hypothesised that BMPs acti-
vate their cognate receptors and trigger the Smad signaling cascade, causing a
reduction in proliferation and increased expression of markers of neural differ-
entiation, with no effect on cell viability. In fact, blocking endogenous BMP4
reduces Smad signaling 37 and increases glioblastoma cell growth, perhaps by
regulating the balance between proliferation and differentiation, and favouring
the production of the differentiated astroglial-like cells normally found within
glioblastomas. The authors surmise that BMP4 may reduce the frequency of
tumour-initiating stem cell-like cells by decreasing symmetric cell cycles that
generate two identical cells on division, triggering differentiation of a subpop-
ulation of tumour-initiating stem cell-like cells or blocking their proliferation
and progeny, which, although not mutually exclusive events, could all con-
tribute to reducing the tumour-initiating stem cell-like population. Thus, the
signaling system constituted by BMPs and their receptors may also act as a
key inhibitory regulator of tumour-initiating, stem-like cells in glioblastomas,
other than controlling the activity of normal brain stem cells. Importantly,
the results of the study by Piccirillo et al also identified BMP4 as a novel,
non-cytotoxic therapeutic effector, which may be used to prevent growth and
recurrence of glioblastomas in humans [392].
Both these studies added depth to the cancer stem cell hypothesis, illustrat-
ing the potential of re-examining cancer under this new light and highlighting
the importance in cancer research of dissociating solid tumour samples into
single cell suspensions to purify the stem cell fraction and test its response
to treatment. Improved purification of the tumour, however, will be required
37 A signaling system that involves the activation by membrane receptor protein kinases
bound by the TGF-β ligand, of a family of receptor substrates, the Smad proteins, that
assemble into multi-subunit complexes to go into the nucleus and activate transcription.
This signaling pathway regulates a wide variety of cell-specific responses, depending on what
is "the cellular context" that the TGFβ family members and multifunctional hormones are
acting in [321].
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