129been shown to interfere with the transdifferentiation of GSCs into endothelial cells and
increased their sensitivity to radiation damage (Wang et al. 2010a; Fan et al. 2010 ).
Nitric oxide (NO) has been shown to activate notch signaling pathway and maintains
a stem-like phenotype in tumors. Along with NOTCH1 overexpression, GSCs also
express NO receptor, sGC and are often found in close proximity to endothelial cells
that express endothelial nitric oxide synthase (eNOS) (Charles et al. 2010 ).
Tumor cells have also been reported to form a matrix embedded network capable
of conducting fluids within the tumor through a process termed as “Vascular Mimicry”.
CD133+ GSCs have been reported to form tube networks in in vitro 3D matrigel
experiments and GSCs have been reported to form tubular structures of vascular chan-
nels in tumors in vivo (El Hallani et al. 2010 ). Knockdown of VEGFR-2 in GSCs
resulted in the loss of the ability to form these tubular structures and hypoxia is
thought to play an important role in this process by upregulating CD144 expression in
GSCs through HIF-1α and HIF-2α (Mao et al. 2013 ; Yao et al. 2013 ).
7.4.2 Hypoxic Niche
In healthy brain tissue, the normal physiological oxygen concentration ranges
between 12.5 and 2.5%. GBM tissue however shows regions of mild hypoxia (2.5–
0.5%) and severe hypoxia (0.5–0.1%) (Evans et al. 2004 ). It is hypothesized that the
oxygen tension gradient within a tumor niche plays a vital role in differentiation of
cells. The cells present in the periphery of tumor masses are thought to exhibit low
proliferation rate, low levels of HIF1α and increased angiogenesis. The cells present
at the tumor core are thought to exist in near anoxic conditions with very low pro-
liferation rates and high levels of HIF1α. Cells present in the intermediate region of
tumors are thought to high proliferation rate, form neurospheres in hypoxic condi-
tions and show increased levels of expression of VEGF, Glut1 and carbonic anhy-
drase IX (CAIX) (Pistollato et al. 2010 ). Therefore, the presence of intratumoral
hypoxia promotes the existence of a pool of stem-like cancer cells at the core of the
tumor which are often resistant to radio- and chemo- therapies.
The importance of hypoxia in maintaining the differentiation state and prolifera-
tion of normal stem cells within their niches and its mechanism is well established.
Within the bone marrow, hematopoietic stem cells (HSCs) migrate to hypoxic
niches where they are maintained in a state of quiescence by the hypoxia induced
protein, osteopontin (Stier et al. 2005 ). Severe hypoxia also prevents the differentia-
tion of NSCs and embryonic stem cells without affecting their proliferation while
also improving the generation of induced pluripotent stem cells (iPSCs) (Mathieu
et al. 2014 ).
Neovascularization within GBM tissue often results in the formation of disorga-
nized, chaotic and highly torturous blood vessels which are unable to effectively
supply the entire tumor tissue with oxygen and nutrients. The lack of uniform oxy-
genation and the high proliferative rate of tumor cells results in the formation of
regions of pseudopalisading necrosis that develop in order to protect the surrounding
7 Glioblastoma Stem Cells and Their Microenvironment