Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.4 Pathways Involved in Glioblastoma Introduction
AKT amplification might be refractory. Also, the co-amplification exhibited
by multiple RTKs in the same glioblastoma sample may be tailored with anti-
RTK therapies to specific patterns of RTK mutation [326].
PTEN is a major tumour suppressor that is inactivated in 50% of high-grade
gliomas by mutations or epigenetic mechanisms, each resulting in uncontrolled
PI3K signaling [154]. PTEN expression is completely extinguished in tumour
cells of hGFAP-Cre + ;p53 lox/lox ;Pten lox/+ GEMMs 21 with developed anaplastic
astrocytomas and glioblastomas, but it is present in the surrounding normal
tissue and vessels supplying tumour tissue. Such LOH effect is very frequent in
human high-grade gliomas [549]. PTEN is located in the long arm of chromo-
some 10 and acts as the central negative regulator of the PI3K/AKT pathway
due to its lipid phosphatase activity that affects RTK signaling [84,99,111].
As a consequence, the RTK/PI3K pathway is commonly affected by the bial-
lelic inactivation of PTEN or LOH of the long arm of chromosome 10. Loss
of PTEN most often results in constitutive activation of AKT1 but is not, in
mature astrocytes, sufficient to drive proliferation and initiate gliomagenesis
in the absence of other mutations. This suggests that the PI3K/AKT pathway
is not sufficiently stimulated by the absence of its main negative regulator to
elevate pathway activity in astrocytes [100]. Furthermore, PTEN may act to
suppress transformation and tumour progression beyond regulation of PI3K
signaling. In a study by Shen et al [453], quiescent cells from mouse model
cell systems 22 harboured high levels of nuclear PTEN, which appeared to fulfill
important roles in the maintenance of genomic integrity, through centromere
stabilisation and promotion of DNA repair [453]. In other studies, a number
of PTEN point mutations found in familial cancer predisposition syndromes
had no effect on enzyme activity and lied within important sequences for the
localisation of PTEN. Analysis of such mutants has confirmed that aberrant
sequestration of PTEN into either the nucleus or the cytoplasm compromises
its tumour suppressor function [117,154,495].
21 In the study by Zheng et al [549], the hGFAP-Cre transgene was used to delete p53 alone
or in combination with Pten in all CNS lineages using conditional p53 and Pten alleles, with
modelling efforts directed towards the Pten lox/+ genotype since broad CNS deletion of Pten
results in lethal hydrocephalus in early mouse postnatal life.
22 This mouse system included mouse embryonic fibroblasts and mouse embryonic stem
cells.
26