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GBMs due to endothelial derived factors (Heddleston et al. 2011 ; Jhaveri et al.
2016 ). In addition, CD133+ GSC population has also been reported to contain a
CD144+ (vascular endothelial-cadherin) cell population with the CD133+/CD144+
cell population showing an overexpression of pro-vasculogenesis markers such as
CD31, CD105, CD 34 and VEGFR-2 (Wang et al. 2010b; Soda et al. 2011 ). In addi-
tion, circulating bone marrow derived cells have also been reported to be present
within GBM vasculature but recent reports evaluating such transdifferentiating
GSC or bone marrow derived cell populations have revealed that their presence
within tumor vasculature is rare and might vary among tumors (Hardee and Zagzag
2012 ). GSCs have also been reported to transdifferentiate into pericytes but further
investigation is needed to determine the role of such pericytes in tumor neovascular-
ization (Cheng et al. 2013 ).
Nestin+/CD133+ stem-like cells within GBMs (GSCs) have been reported to
reside in close proximity to capillary networks within niches in GBMs that resemble
the neural stem cell niche. Endothelial and other vascular cells are thought to play a
role in the maintainance of differentiation and proliferation of NSCs within the
neural stem cell niche and the same is thought to occur in the case of GSCs. The
dedifferentiation of GSCs into endothelial cells or the migration of endothelial cells
that do not participate in the process of neovascularization towards GSCs could pos-
sibly serve as a mechanism to secrete factors to prevent maturation and proliferation
of GSCs, which often impedes efficacy of radio- and chemo- therapies (Fidoamore
et al. 2016 ; Calabrese et al. 2007 ). GBM cells have also been reported to infiltrate
areas around brain vasculature and incorporate blood vessels into the tumor in a
process termed as “Vascular Co-option”. These tumor incorporated blood vessels
are thought to undergo apoptosis inducing a state of hypoxia within these regions
which could possibly maintain GSCs and stimulate the secretion of pro-angiogenic
factors (Holash et al. 1999 ; Reiss et al. 2005 ; Liebelt et al. 2016 ).
SDF-1 or CXCL12 maintains NSCs in their niche and regulates their trafficking
and homing within the brain. SDF-1 is a ligand for CXCR7 and is the only ligand
for CXCR4, which is secreted either as an autocrine or paracrine factor in several
cancers including GBM. Apart from promoting cancer cell proliferation, invasion,
angiogenesis and cancer stem cell maintainance, SDF-1 has been shown to recruit
bone marrow derived cells (BMDCs) that promote neovascularization, such as
CXCR4 secreting endothelial precursor cells. GSCs express both CXCL12 and its
receptors and endothelial cells within the brain have been reported to express
CXCL12 to recruit GBM cells. The CXCR4/CXCL12 signaling axis is particularly
high in pseudopalisading regions and invasive ends of GBM, indicating their impor-
tance in GSC maintainance and movement (Doetsch 2003 ; Sun et al. 2010 ).
CXCL12 has also been reported to regulate tumor apoptosis by activating NF-κB,
which reduces TNFα production. Radiation therapy, chemotherapy and treatment
by VEGFR inhibitors activates CXCL12/CXCR4 pathway, resulting in the recruit-
ment of myeloid BMDCs and promotion of angiogenesis and tumor invasion (Wang
et al. 1996 ; Duda et al. 2011 ).
Notch signaling pathway is yet another way in which the perivascular niche plays
an important role in regulating differentiation state of GSCs. NOTCH1 silencing has
A. Sattiraju et al.