Biomedical Engineering Reference
In-Depth Information
collections of cells (neurospheres) that are multipotential and self-renewing.
Interestingly, type C cells exposed to exogenous EGF for 6 days in vivo
demonstrate unusually high motility, migration along blood vessels and white
matter tracts, and expression of EGFR and tenascin—all hallmark character-
istics of gliomas. Furthermore, type C cell proliferation is tightly regulated by
the CDK inhibitor p27Kip1, a G
1
regulator of the cell cycle. Elimination of this
regulator selectively increases the number of type C cells, concomitant with a
decrease in the number of type A neuroblasts (Doetsch et al. 2002b). Interest-
ingly, a low expression level and high degradation activity of p27 are indepen-
dent poor prognostic factors in patients with malignant gliomas (Zolota et al.
2008). Taken together, these data suggest that not only could type C cells be a
driving force behind neurosphere formation, but that the response of type C
cells to exogenous growth factors may serve as a model system to study tumor
initiation and invasion in the adult brain. Importantly, the human homologue
to the C cell type has yet to be identified.
8 Implications for Brain Tumor Therapy
Based upon the cancer stem cell hypothesis, any brain tumor therapy that fails
to eradicate cancer stem cells will result in the recurrence or regrowth of the
remaining tumor stem cells, leading to eventual disease progression (Schulen-
burg et al. 2006). As this cell population is characterized in more detail, studies
have suggested that brain tumor stem cells are particularly resistant to the
standard adjuvant therapies for gliomas, including radiation therapy (Bao
et al. 2006b) and the alkylating agent, temozolomide (Clement et al. 2007).
Thus, new therapies that target the most resilient fraction of the tumor are
needed to improve treatment response.
One such strategy relies upon our understanding of mechanisms governing
the fate of adult neural stem cell progeny, where factors that inhibit prolifera-
tion of neural stem and progenitor cells could be directed toward brain tumor
stem cells. Bone morphogenetic proteins (BMPs) are a family of cytokines with
a complex set of effects on neural stem and progenitor cells (Varga and Wrana
Fig. 1 (continued) radial glia, as well as C cells and APCs, may represent a source of gliomas.
In the external granule layer (EGL) of the developing cerebellum, transit-amplifying cells
similar to type C cells have also been suggested as a source of medulloblastomas. Migrating
neuroblasts (Nb) represent a population comparable to OPCs, but along a neuronal lineage,
and thus may generate tumors with neuronal components, including gangliocytomas, gang-
liogliomas, and neurocytomas. In the subventricular zone, astrocytic neural stem cells (type B
cells) may themselves be a source of gliomas, as might their C cell progeny, which also could be
a source of primitive neuroectodermal tumors (PNETs) and gliomas. These proposed lineage
relationships connecting the ventricular and subventricular zones to brain tumors remain
hypothetical and as of yet unproven
