Biomedical Engineering Reference
In-Depth Information
produce several types of progeny, robust proliferative potential, and association
with blood vessels and white matter tracts. CD133 (also known as prominin) is
a cell surface marker associated with stem-like cells found in both the hema-
topoietic and central nervous system (Singh et al. 2003). Interestingly, CD133
is also expressed by radial glia and neuroepithelial cells (Pfenninger et al.
2007). On the basis of CD133 expression, cancer stem cells and normal adult
neural stem cells can be isolated by cells sorting and shown to self-renew and
exhibit multipotency (Singh et al. 2004a; Galli et al. 2004). The identification
of this population suggests that these cells represent the tumor-initiating
fraction of human gliomas (Singh et al. 2004b) and has led to the emergence
of the 'cancer stem cell hypothesis' for brain tumors.
5 Susceptibility of Stem and Progenitor Cells to Transformation
That neural stem cells are potentially susceptible to transformation is sug-
gested by the fact that, in animal models, regions of the brain that are highly
proliferative—including areas with neural stem cell populations—are more
sensitive to chemical or viral oncogenesis than are areas with a low proportion
of proliferating cells. In canine and rodent brains, for example, avian sarcoma
viral transformation (Hopewell 1975) or systemic exposure to the carcinogen
N-ethyl-N-nitrosourea (ENU; Pilkington and Lantos 1979; Lantos and Pilk-
ington 1979; Lantos 1977) preferentially leads to tumor formation in the
proliferative subventricular zone rather than in nonproliferative regions of
the brain. In one study, intraventricular inoculation with avian sarcoma virus
in neonatal canine brains initially led to periventricular glioma microfoci, but
as the tumors grew, their continuity with the subventricular zone diminished
until, at day 10 after inoculation, they were found in the deep white matter
without apparent connection to the subventricular zone (Pilkington and
Lantos 1979). Migration of transformed germinal zone cells may be a mechan-
ismby which human gliomas arise fromneural stem cells but then go on to lose
any evidence of continuity with these regions. Similarly, infusion of EGF or
PDGF into the lateral ventricle of the adult brain results in the elevated
proliferation of progenitor cells and the formation of highly invasive cells or
glioma-like masses (Jackson et al. 2006; Doetsch et al. 2002a). Mouse models
in which progenitor cells are exposed to high levels of PDGF or EGF exhibit
the formation of tumors that are histologically similar to human gliomas,
and alterations in the PDGF and EGF pathways have frequently been found
in human glioma (Feldkamp et al. 1997). Finally, mice lacking the tumor
suppressors p53 and NF1 in the CNS develop early lesions that are associated
with the SVZ and that progress to tumors resembling human malignant
astrocytomas (Zhu et al. 2005).
As the postnatal brain ages, the germinal region neural progenitor prolifera-
tion appears to be restrained by increased levels of cell-cycle inhibitor proteins.
