Biomedical Engineering Reference
In-Depth Information
been shown to kill cancer cells; so the pathways are potential targets for anticancer
drugs (
22,
23
). The researchers caution that Hedgehog and Wnt blockers could
affect normal processes that use these signals, including normal tissue repair,
although short-term studies in mice have not yet found toxic side effects (
23-
25
) .
Activation of the Wnt pathway is also associated with brain tumors. In particular,
a subset of medulloblastomas has been reported to harbor mutations in
b -catenin,
Axin,
or
APC
(
26
). Since these tumors have a distinct phenotype and molecular
profile from medulloblastomas associated with hedgehog pathway mutations,
they may arise from a distinct set of progenitors. To date, there have been no
reports of Wnt pathway mutations in brain tumors outside the cerebellum.
However, given the importance of Wnt signaling in self-renewal of progenitors
throughout the brain, it is worth considering whether dysregulation of this
pathway occurs in other types of brain tumors as well.
•
Other signaling pathways
The importance of these signaling pathways (JAK-STAT in embryonic stem
cells, Notch, Jagg 1) in adult stem cells versus NSCs is under investigation.
Stimulation of human epidermal differentiation by delta-notch signaling at the
boundaries of stem-cell clusters has been found by two investigators, indepen-
dently (
27,
28
). While the canonical Notch signaling pathway is deceptively
simple, the consequences of the Notch activation on cell fate are complex and
context dependent. The manner in which other signaling pathways cross-talk
with Notch signaling appears to be extraordinarily complex. For example, the
soluble Notch ligand, Delta-Fc, causes glial lineage determination by neural
crest stem cells within 1 day in culture (
28
). One can hypothesize that these
pathways could be involved in glial tumor growth in some instances. So, each
type of brain tumor probably has different mechanisms of extensive growth and
dedifferentiation. Therefore, this part of neurological stem cell therapy might be
the most tricky to adjust since tumors vary from glioblastoma, meduloblastoma,
and ependymoma to astrocytoma. It is impossible to expect general therapeutic
approach for each of them. Therefore, the basic research in this field at molecular
level is essential and the therapeutical management quite distinctive. Obviously,
in this case the classical stem cell transplantation is not the answer.
Transcription Factors and Their Repressors
•
Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor
proliferation
Bmi-1 regulates self-renewal of progenitors in the central and peripheral nervous
systems (
29
), in part by repressing genes (such as p16Ink4a and p19Arf) that
promote cellular senescence and cell death. In addition,
bmi-1
has recently been
shown to be a target of the Shh signaling pathway and to be required for self-
renewal of neural progenitors in the cerebellum (
30
) . However, the polycomb
family transcriptional repressor Bmi-1 is required for the self-renewal but not for
the differentiation of stem cells in the hematopoietic system and peripheral and
