121astrocytes and pericytes which wrap around endothelial cell tight junctions (Abbott
2002 ; Abbott et al. 2010 ; Agarwal et al. 2013 ; Persidsky et al. 2006 ; Wolburg and
Lippoldt 2002 ). The protective nature of the BBB causes several complications in
delivering effective concentrations of therapies to tumor tissue as it regulates the
extravasation of macromolecules and chemotherapy (Hawkins and Davis 2005 ;
Pardridge 2005 ). GBMs exhibit high genetic heterogeneity due to clonal evolution
of cancer cells making it difficult to target all GBM cells using a single biomarker
targeted therapy that results in cancer cells surviving treatment and ultimate recur-
rence (Patel et al. 2014 ; Bonavia et al. 2011 ; Sottoriva et al. 2013 ; MDM et al.
2010 ). GSCs are thought to exist primarily in hypoxic or necrotic areas which are
often inaccessible by chemotherapy and are thought to be resistant to chemotherapy
due to overexpression of drug efflux pumps and their slow division rate (Seidel et al.
2010 ; Bar et al. 2010 ; Li et al. 2009 ; Heddleston et al. 2010 ; Heddleston et al. 2009 ;
Carmeliet and Jain 2000 ; Dewhirst et al. 2008 ; Pistollato et al. 2010 ; Singh et al.
2004a; Murat et al. 2008a). Radiation therapy is another standard treatment option
for GBM patients but has proven to be ineffective in completely eliminating the
disease (Bao et al. 2006a; Bao et al. 2006b). Radiation causes the creation of free
radicals in oxygenated areas that in turn cause DNA breaks in cells within the expo-
sure field. GSCs are often resistant to radiation therapy as they are thought to exist
primarily in hypoxic regions within the tumors where the creation of high amounts
of free radicals is not possible (Bao et al. 2006a; Wang et al. 2010a). Radiation
therapy also inflicts immediate and long term neuro-cognitive deficits due to dam-
age to surrounding normal neural tissue (Tallet et al. 2012 ; Greene-Schloesser et al.
2012 ; Greene-Schloesser and Robbins 2012 ).
7.1.3 Attempts to Target GSCs and Role of Microenvironment
Strategies to bypass or to enhance the permeability of the BBB in order to deliver
effective concentrations of chemotherapy have shown promise. Furthermore, engi-
neering advances have allowed for limiting radiation exposure and protecting nor-
mal areas of brain (Konofagou et al. 2012 ; Baskar et al. 2012 ; Nhan et al. 2014 ;
Burgess et al. 2014 ; Jordao et al. 2013 ). But strategies to identify GSC specific
biomarkers and the targeting of therapies against them have not been fruitful thus
far. Recent studies have highlighted the importance of the microenvironment includ-
ing paracrine factors secreted within the perivascular niche, hypoxic areas and the
extracellular matrix on the biology and maintenance of GSCs. It is therefore imper-
ative to understand the important pathways within the GSC niche that are critical for
their survival and maintenance. It is also important to identify the nature of origin of
GSCs as it could allow elucidating their biology and understanding extracellular
factors that are critical for their maintainance. In this chapter, we introduce you to
recent finding regarding the GSC microenvironment and highlight critical steps that
could be taken in the future.
7 Glioblastoma Stem Cells and Their Microenvironment