Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
screening models have been poorly predictive of useful therapeutic agents and
may have led to important misinterpretations on the relevance of aberrant sig-
naling pathways within cell lines compared to primary tumours [261].
Nonetheless, cell lines don’t contain the typical mixture of genetically distinct
cells of primary tumours and can therefore be more easily characterised. In
fact, the problematic presence of non-tumour cells in primary tumours, makes
it harder to pinpoint the rare mutations that are not spread uniformly through-
out the tumour [275]. On the basis of this claim, cancer cell line sequencing
efforts are recently flourishing, including works on the commonly studied grade
IV glioma cell line U87MG [101].
With these pros and cons in mind, in the study by Lee et al [261] they went on
to search for a more biologically relevant model system for exploring glioma bi-
ology and for the screening of new therapeutic targets, which they found in neu-
ral stem (NS) cells. These cells have characteristics of continuous self-renewal,
extensive migration and infiltration of brain parenchyma and the potential for
full or partial differentiation, which are lost in glioma cell lines [261,286,347]
and will be discussed in greater detail in chapter three (see Section 3.3).
Classification Systems
Several decades of experimentation on glioblastoma have highlighted that
specific genetic lesions are more commonly observed in certain subclasses of
glioblastoma. Primary glioblastoma typically harbours mutations in the EGFR
receptor tyrosine kinase gene, tumour suppressor PTEN and cyclin inhibitor
CDKN2A, while secondary glioblastoma harbours mutations in Platelet-derived
growth factor (PDGF) and tumour suppressor TP53. However, the latter as-
sociation is now starting to be considered a historical one, since an increasing
number of studies are showing that TP53 mutations occur in a significant
amount of primary glioblastomas [383,549]. These alterations can become pre-
dictive of glioma subclasses. Glioblastomas with intact expression of the PTEN
and EGFR vIII 17 proteins, for example, correlate with increased EGFR kinase
inhibitor response as compared to tumours expressing EGFR vIII but lacking
PTEN [329].
Immunohistochemical markers have been important tools so far in the classifi-
cation and diagnosis of malignant gliomas, with Glial fibrillary acidic protein
(GFAP) and Oligodendrocyte lineage transcription factor 2 (OLIG2) being two
17 The vIII mutant of EGFR is the most common in glioblastoma and results from a
non-random 801bp in-frame deletion of exons 2 to 7 of the EGFR gene [371].
18