Biomedical Engineering Reference
In-Depth Information
Although cell-cycle inhibition may act to prevent hyperproliferation and tumor
development as oncogenic mutations accumulate in an aging organism, this
inhibition also limits the ability of the organism to maintain normal neural
tissue homeostasis. In aging mice, the cell-cycle inhibitor p16/INK4A is
expressed in the SVZ, but this expression is absent in younger mice (Campisi
2007). When p16/INK4A is removed, SVZ cells from aging mice seem to retain
the proliferative potential observed in younger mice (Molofsky et al. 2006). p16/
INK4A is frequently lost or mutated in human gliomas (Ivanchuk et al. 2001),
suggesting that disruption of the regulation of proliferative potential, when
coupled with other oncogenic events, could result in cancer formation. Impor-
tantly, while it has been speculated that brain tumor stem cells arise from SVZ
stem and/or progenitor cells that have sustained oncogenic mutations, no direct
evidence links adult neural stem cells to a glioma cell-of-origin.
The subcortical white matter contains one of the largest populations of
cycling cells in the adult brain (Roy et al. 1999). Progenitor cells in the white
matter are another cellular compartment that may be uniquely susceptible to
transformation. High levels of PDGF expression in the subcortical white matter
of rodents can lead to formation of heterogeneous glioma-like masses that are
driven by a mixture of PDGF expression, tumor-initiating cells, and recruited
local progenitors (Assanah et al. 2006). Interestingly, the pattern of infiltration
seen in this model demonstrates a predilection for fiber tracts, as seen in both
human gliomas and glial progenitors during brain development (Kakita and
Goldman 1999; Kakita et al. 2003), raising the possibility that the infiltrative
capacity of gliomas may represent a re-expression of a neonatal glial progenitor
phenotype.
6 Shared Immature Expression Profiles Among Brain Tumors
and Stem Cell Niches
Postnatal germinal regions such as the ventricular and subventricular zones
contain unique cytoskeletal proteins, tumor suppressor genes, growth factors,
transcriptional signaling cascades, and telomerase expression patterns that are
shared by glioma cell populations. These unique phenotypes, along with tumor
location and age of onset, suggest possible lineage relationships associating
normal germinal zone progenitor cell types with specific histologic subtypes
of brain tumors.
6.1 Cytoskeletal Proteins
Nestin is an intermediate filament widely expressed by progenitor and stem cells
during development (Wiese et al. 2004). Although it is relatively prevalent at
birth, its expression is downregulated in the adult brain and becomes restricted
