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7.1 Introduction
7.1.1 Disease Classification and Histopathology
Glioblastoma (GBM) is classified according to the 2007 WHO classification as a
grade IV (high grade) astrocytoma (Louis et al. 2007 ). GBM is the most common
and aggressive primary (arising de novo) malignant astrocytoma which is often
characterized by extensive microvascular hyperplasia, hypercellularity, prolifera-
tion, diffuse infiltrating margins and necrotic foci, often surrounded by pseudopali-
sading cells, an ominous histopathological feature that distinguishes them from
non-malignant “low-grade” gliomas (grade I and II) (Brat et al. 2004 ; Bissell and
Radisky 2001 ; Rong et al. 2006 ; Van Meir et al. 2010 ). These pseudopalisades have
previously been reported to be highly hypoxic and instigate microvascular hyper-
cellularity through secretion of hypoxia inducible factors (HIFs), vascular endothe-
lial growth factor A (VEGF-A) and interleukin 8 (IL-8). Using microarray analysis,
The Cancer Genome Atlas (TCGA) researchers were able to identify genomic
changes which drive GBM tumor development and classified the disease into clas-
sical (EGFR high, mutated TP53 low), proneural (mutated TP53 high, mutated
IDH1 high, mutated PDGFA high), mesenchymal (mutated NF1 high, frequent
mutations of PTEN and TP53) and neural subtypes (mutations in same genes as
other subgroups; expression of neural genes) (Verhaak et al. 2010 ).
7.1.2 Therapeutic Challenges for Treating GBMs
Standard treatment strategies for GBM patients in the clinic include surgical resec-
tion, radiotherapy, chemotherapy with temozolomide (TMZ) and the recently FDA
approved oscillating electric field therapy (Hottinger et al. 2014 ; Weller et al. 2012 ).
Regardless of efforts to increase safety and efficacy of these treatments in the clinic,
the median overall survival of patients has only extended to about 14.6 months.
GBM is a highly infiltrative disease with cancer cells migrating extensively into
surrounding normal neural tissue. It is therefore not possible to remove all tumor
cells from patients through surgical resection, as they have been observed 2–3 cm
from the original site of the tumor. Importantly, these invasive cells that are left
behind after surgery close to the margins of the resection cavity give rise to even
more aggressive tumors (Chaichana 2014 ; Eyupoglu et al. 2013 ; Yong and Lonser
2011 ). These cells that repopulate and maintain GBM tumors after gross surgical
resection are thought to be undifferentiated glioblastoma stem cells (GSCs) (Jackson
et al. 2015 ; Lathia et al. 2015 ; Ahmed et al. 2013 ; Cho et al. 2013 ). Seeding other
normal regions of the brain with primary GBM cells during resection is another
possible limitation of surgery.
The vasculature within the central nervous system protects neural tissue from
harmful molecules by the formation of a blood-brain barrier (BBB). It comprises of
A. Sattiraju et al.