127tightly regulated balance of various components of the neural stem cell niche that
are responsible for maintaining NSCs. Dysregulation of any one of these compo-
nents could result in a domino-effect which could cause de-regulated proliferation
or differentiation of NSCs and their progenitor cells. Recent studies have also shown
that deletion of Nf1, Trp53 and PTEN in adult neural stem cells and their progenitors
resulted in altered migration of aberrantly differentiated progenitors from
SVZ. These altered cells gave rise to tumors in the brain instead of migrating and
terminally differentiating into neurons. Aberrant mutations within cells of the NSC
niche or NSCs themselves could results in GSCs, which may migrate elsewhere to
form tumors or give rise to cells with similar differentiation potential through asym-
metric division. These progeny can then in turn migrate to other regions of the brain
to initiate tumors. Therefore, the site of origin of GSCs may not be the site of origin
of GBMs (Alcantara Llaguno et al. 2015 ).
7.4 Role of Tumor Microenvironment in the Origin
and Maintenance of De-Differentiated Somatic
GBM Cells7.4.1 Perivascular Niche
Extensive neovasculogenesis and abnormal morphology of vasculature is a com-
mon characteristic of GBMs. GBMs exhibit various forms of neovascularization
which allow supply of essential nutrients and oxygen to tumor cells (Jhaveri et al.
2016 ).
The process of de novo formation of blood vessels in situ, termed as
“Vasculogenesis” is thought to occur primarily during fetal development. However,
recent research has shown that vessel formation can also result from circulating
endothelial cells, tumor associated macrophages (TAMs), Tie-2+ monocytes and
GSCs (De Palma et al. 2007 ; Venneri et al. 2007 ; Folkman and Shing 1992 ).
Angiogenesis, a process of stimulating the sprouting of new blood vessels from
preexisting vasculature is a critical step in tumor development and migration. GBMs
are often characterized as having significantly increased angiogenesis and studies
have indicated GSCs to play an important role in this process (Jhaveri et al. 2016 ).
GSCs have been shown to overexpress factors that promote blood vessel formation
such as VEGF and SDF-1α and their knockdown has been shown to significantly
affect vessel formation in tumors in vivo (Folkins et al. 2009 ). 20–90% of CD31+
endothelial cells were found to carry the same genetic mutations as tumor cells in
human GBM samples (such as amplification of EGFR and chromosome 7) and
GSCs cultured in endothelial cell culture conditions have been reported to transdif-
ferentiate into CD31+ and Tie-2+ endothelial cells (Ricci-Vitiani et al. 2010 ).
Studies also showed that co-implantation of GSCs and endothelial cells in immuno-
compromised mice resulted in accelerated initiation and growth of orthotopic
7 Glioblastoma Stem Cells and Their Microenvironment