Biomedical Engineering Reference
In-Depth Information
serve as critical regulators of tumorigenesis. Although these programs coordi-
nate the use of normal cellular components, their timing, order, and magni-
tude are probably abnormal in tumorigenic states.
Sonic Hedgehog (Shh) is a key regulator of progenitor proliferation in the
external granular layer (EGL) of the cerebellum (Wechsler-Reya and Scott
1999; Mullor et al. 2002). Misregulation of this pathway by mutation of the
Shh receptor, Patched, or constitutive activation of Smoothened results in
medulloblastoma formation, linking them with cerebellar granule cell precur-
sors (Kenney et al. 2003; Kim et al. 2003; Rubin and Rowitch 2002). Further-
more, granule cell precursors of the EGL can be considered a type of transit-
amplifying cell (C cell), derived from primary progenitors of the rhombic lip.
Therefore, the direct effect of Shh misregulation in medulloblastoma is a good
example of the possible role of transit-amplifying cells as a cell-of-origin in
human brain tumors.
Hedgehog signaling is also implicated in both glioma and progenitor pro-
liferation, as it activates two zinc-finger transcription factors (Gli1 and Gli2)
and suppresses Gli3 function, which, in turn, regulate progenitor cells by
promoting cell-cycle entry and DNA replication. In the adult CNS, Gli1 is
expressed by neuronal progenitors in the SVZ, where the sonic hedgehog
(Shh)-Gli pathways maintain the type B cell population and facilitate the
survival and proliferation of their progeny (Palma et al. 2005). Importantly,
Gli1 is expressed in both low-grade and high-grade gliomas, and the Shh-Gli
pathway may mediate the initiation and maintenance of these tumors as it does
for neural stem cells (Dahmane et al. 2001). Therefore, as would be expected,
treatment with cyclopamine, a hedgehog pathway inhibitor, represents a poten-
tial avenue of glioma stem cell control (Bar et al. 2007).
7 Transit-Amplifying Type C Cells as a Glioma Cell-of-Origin
Although it remains possible that neuroepithelial cells, radial glia, type B cells,
type A cells, and even a putative astrocyte precursor cell (APC) could each serve
as a glioma cell-of-origin (see Fig. 1), it seems likely that a type C cell would be
most commonly implicated in a fashion similar to the transit-amplifying cells of
the EGL. As mentioned above, the EGF signaling pathway plays an important
part in both gliomagenesis and adult neural stem cell regulation. Amplification
of the EGFR gene is associated with the formation of high-grade gliomas
(Kuan et al. 2001; Lassman 2004), and activation of EGFR promotes the
growth of both astrocyte precursors and neural stem cells (Doetsch et al.
2002a). As many as 50% of high-grade astrocytomas demonstrate EGFR
amplification, and EGFR activation may drive the transformation process
in the development of gliomas. In the SVZ of the adult rodent, the majority
of EGF-responsive cells correspond to the rapidly dividing transit-amplifying
C cells. In response to EGF exposure in vitro, these cells give rise to spherical
