Biomedical Engineering Reference
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to the SVZ postnatally. Interestingly, following ENU exposure, undifferen-
tiated Nestin+ cells are present during the earliest periods of periventricular
tumorigenesis and these cells persist throughout tumor progression (Jang et al.
2004). Similarly, Nestin+ SVZ cells removed at birth can undergo spontaneous
immortalization after in utero exposure to ENU (Savarese et al. 2005). Nestin+
cells also exist in human gliomas (Yang et al. 2008), further supporting the
hypothesis that neural stem cells may be implicated in glioma formation. It
remains unclear, however, whether the expression of Nestin is a genetic aberra-
tion or a normal property of the precursor cell fromwhich the tumor originated.
Furthermore, since Nestin is nearly ubiquitously expressed by neural stem and
progenitor cells at all stages of development, its utility as a stem cell or brain
tumor stem cell marker is limited.
Doublecortin is a microtubule-associated protein that is expressed by the
SVZ type A cells, as well as by migrating young neurons generated by neuroe-
pithelial cells and radial glia (Nacher et al. 2001). While many of these cells are
postmitotic, type A cells in the SVZ function as neuroblasts and divide to
generate additional neuronal progeny (Luskin 1998). Doublecortin has also
been shown to be preferentially expressed in high-grade gliomas (Daou et al.
2005) and glioneuronal tumors such as gangliogliomas (Becker et al. 2002).
Interestingly, overexpression of doublecortin in glioma cell lines appears to
protect tumor cells from severe oxygen and glucose deprivation (Santra et al.
2006). Taken together, these findings raise the possibility that neuronal pre-
cursors, possibly similar to type A cells, may be implicated not only in glioma-
genesis, but also in the formation of glioneuronal tumors, many of which
develop early in life.
6.2 Tumor Suppressor Genes
p53 is a tumor suppressor gene expressed in SVZ cells (Gil-Perotin et al. 2006)
and frequently deleted or mutated in gliomas (Sidransky et al. 1992). Loss of
p53, alone, is not sufficient for tumor formation, but may predispose SVZ cells
to tumorigenesis. Specifically, it increases the number of adult neural stem cells
and neuroblasts and induces the formation of periventricular hyperplasia in
adult SVZ, while also impairing differentiation (Gil-Perotin et al. 2006). Thus,
loss of p53 confers a proliferative advantage to the slow- and fast-proliferating
populations in adult SVZ. Synergistically, prenatal exposure of p53 / mice to
ENU leads to the formation of glioma-like tumors in the adult SVZ (Katayama
et al. 2005). Here, tumor formation has been suggested as the result of amplified
self-renewal, faster cell division of the relatively quiescent population, and
impaired differentiation of multipotential progenitors. Based upon this
model, transformation of the adult SVZ is preceded by recruitment of the
quiescent self-renewing (type B cell) population to the fast-proliferating (type
C cell) compartment, which in turn may be unable to differentiate along distinct
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