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The
Role of PTEN Tumor Suppressor in Brain Growth and Tumor Development
Caroline Gregorian, Matthias Groszer, Qing Yue, Xin Liu, Hong Wu
University of California, Los Angeles, Los Angeles, CA
Glioblastoma Multiforme (GBM)
is one of the most common and aggressive forms of human brain
tumors.
Genetic aberrations of the PTEN
tumor suppressor gene (phosphatase and tensin homologue deleted on
chromosome 10) are found in more than 30% of primary GBM.
PTEN is a lipid/protein
phosphatase that antagonizes the PI3K/AKT signaling pathway.
Loss of PTEN leads to enhanced
cell proliferation, survival, and invasiveness.
In order to study PTEN's role
in brain growth and tumorigenesis, we generated PtenloxP/loxP mice
and crossed them to different brain-specific Cre strains.
Mice lacking PTEN in embryonic
day 14 (E14) neural stem/progenitor cells (NSPC) develop enlarged
brains due to increased cell proliferation, decreased cell death, and
enlarged cell size.
In vitro cell cycle
studies on NSPCs from E14 Pten-/- and wild-type brains show
that loss of PTEN facilitates the G0-G1 cell cycle transition.
Due to the perinatal lethality
of the mutant animals, PTEN’s role in regulating adult neural stem
cells (NSC) and tumorigenesis could not be evaluated.
Therefore we generated mouse
models with Pten deletion in the brain during late development
and in the adult.
Our preliminary results
demonstrate an enhanced proliferation index in cortical and
hippocampal regions and an increased cell number in the dentate gyrus
upon Pten deletion. These mice suffered from progressively
increased brain size, leading to brain pressure complications and
subsequent death without obvious GBM formation.
Thus, longer survival time may
be necessary for tumor development.
Therefore, we have
stereotactically injected helper-dependent adenovirus expressing Cre
(HDA-CRE-YFP) into adult PtenloxP/loxP mice.
Since human GBM tumors initiate
focally and may arise from mutated precursor/stem cells, we have
chosen to focally delete Pten in the proliferation permissive
areas of the subventricular zone (SVZ) and dentate gyrus (DG).
Our preliminary in vivo
data demonstrates our accuracy in the stereotactic delivery of
HDA-CRE-YFP into the DG and SVZ.
In addition, PTEN’s deletion
in these areas results in increased cell proliferation in postnatal
animals.
Hence PTEN might be important
for the regulation of adult NSC proliferation.
Furthermore, loss of PTEN in
NSCs may be an important genetic event contributing to GBM
pathogenesis.
Copyright © 2005 American
Association for Cancer Research. All rights reserved.
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