Biomedical Engineering Reference
In-Depth Information
lineages. Several other signaling pathways also shape this response, as p53
/
mice form gliomas following both PDGF overexpression (Hesselager et al.
2003) and Ras activation (Zhu et al. 2005). Interestingly, among non-neuro-
genic astrocytes, loss of p53 combined with constitutive EGF-receptor (EGFR)
activation does not lead to tumorigenesis, even though these cells have the
ability to generate gliomas when expression of constitutively active EGFR is
associated with loss of other cell-cycle genes, such as Ink4a and Arf. Of note,
60% of malignant human gliomas show abnormalities at the Ink4a/Arf locus
and Ink4a/Arf mutations have also been detected in cells isolated from ENU-
injected animals (Savarese et al. 2005). These observations therefore identify at
least two distinct mechanisms of gliomagenesis: one that is Ink4a/Arf dependent
and p53-independent and another that is p53-dependent. This is consistent with
human glioma studies suggesting that p53 and Ink4a/Arf mutations are
mutually exclusive (Bachoo et al. 2002).
Early inactivation of p53 has also been shown to cooperate with the neurofi-
bromatosis-1 (NF1) tumor suppressor gene mutation, inducing malignant astro-
cytoma formation in a mouse tumor model (Zhu et al. 2005). The NF1 tumor
suppressor product neurofibromin is a functional Ras GTPase-activating protein
and its loss results in abnormal activation of Ras, a central mediator of receptor
tyrosine kinase (RTK) signaling. Mice that carry germline mutations in both p53
and NF1 developed both low- and intermediate-grade astrocytomas. These
astrocytomas express Nestin, the progenitor-associated intermediate filament,
and were associated with the SVZ, suggesting that SVZ cells are most susceptible
to p53/NF1-mediated astrocytoma formation.
PTEN (phosphatase and tensin homologue deleted on chromosome 10)
is a recognized tumor suppressor mutated in many gliomas. The PTEN
protein is a phosphatidylinositol phosphate (PIP) phosphatase that lowers
PIP3 levels and enhances the rate of apoptosis. PTEN also decreases cell
motility via G protein-coupled mechanisms. PTEN is expressed by neuroblasts
during neuronal differentiation (Lachyankar et al. 2000). Using a knockout
mouse model, PTEN has also been shown to regulate type A cellular migration
from the SVZ to the olfactory bulb (Li et al. 2003). Importantly, loss of PTEN
increases proliferation in the SVZ and decreases apoptosis, indicating that
PTEN is a negative regulator of progenitor cell proliferation. As such, PTEN
is a common pathway shared by both SVZ type A cells and secondary
glioblastomas.
6.3 Growth Factors
Growth factor signaling pathways play a critical role in both gliomagenesis and
germinal zone regulation. For example, nearly half of all high-grade astrocyto-
mas demonstrate EGFR amplification, while EGFR mutation is a classic step
in the development of primary glioblastomas. EGF-responsive C cells and a
