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6.4.2.2 CSCs-Vasculature Interactions
Extensive interplay between CSCs and endothelial cells (ECs) has been identified,
one example already being examined regarding the generation of laminin α2 from
endothelial cells which can bind to integrin receptors on the CSCs. EC mediated
pathophysiological processes such as angiogenesis and hallmark functions of CSCs
such as self-renewal are interconnected and elimination of endothelial cells can lead
to detrimental effects for GSCs, driven in part from Notch signaling (Hovinga et al.
2010 ). The endothelial secretome can preserve CSCs properties, promoting mTOR-
dependent survival (Maria Galan-Moya et al. 2011 ) or activating Notch signaling
via nitric oxide (NO) produced by nitric oxide synthase 3 (NOS3) (Charles et al.
2010 ). High levels of NO can also be produced endogenously in GSCs, which have
elevated nitric oxide synthase 2 (NOS2) expression, compared with non-GSCs and
normal neural progenitor cells, thus promoting their tumorigenic profile (Eyler et al.
2011 ). Vice versa, CSCs produce proangiogenic factors such as vascular endothelial
growth factor (VEGF) and stromal-derived factor 1 (SDF1), boosting EC activation
and migration and supporting angiogenesis/vasculogenesis (Bao et al. 2006 ; Folkins
et al. 2009 ; Oka et al. 2007 ; Ping et al. 2011 ). VEGF secretion can be promoted by
the chemokine CXCL12 (SDF1), whose receptor’s (CXCR4) expression is elevated
in GSCs and activates a PI3K/Akt dependent pathway (Ping et al. 2011 ). Interestingly,
VEGF is part of an autocrine VEGF–VEGFR2–Neuropilin-1 signaling pathway,
indicating that CSCs can regulate, sustain and promote their own growth rate
through the expression of vascular endothelial growth factor receptor 2 (VEGFR2)
(Hamerlik et al. 2012 ).
In addition to the effect of secreted factors exchanged between ECs and CSCs,
direct interactions between these two distinct cell types have been studied. Notch
signaling plays a pivotal role in EC-CSC crosstalk and can be activated through
Notch ligand independent way (e.g. nitric oxide) or through ligand dependent man-
ner. Nestin is co-expressed with Notch receptors, Notch1 and Notch2, on CSCs
which have elevated levels of Notch activity in conjunction with constitutive activa-
tion of the STAT3/NF-κB signaling pathway and up-regulation of STAT3- and
NF-κB-dependent genes (Garner et al. 2013 ; Zhu et al. 2011 ). On the other hand,
ECs express Notch ligands Delta-like 4 (DLL4) and Jagged-1 (JAG1) and enhance
the self-renewal of adjacent Notch receptor-expressing stem cells properties through
juxtacrine signaling (Zhu et al. 2011 ). Recently, the binding of integrin αvβ3,
expressed on ECs to the RGD-peptide in the extracellular domain of L1CAM on
CSCs, was shown to mediate an FGF2-induced cascade involving the activation of
BMX, FAK, p130CAS and the downstream effectors ERK and JNK. It resulted in
enhanced formation of ECs networks and their chemotactic attraction by FGF2;
thereby, promoting angiogenesis (Burgett et al. 2016 ). Notch signaling has also
been linked to glioblastoma radioresistance and the utilization of gamma-secretase
inhibitors (GSIs) attenuates this protective effect, sensitizing CSCs to radiation
damage (Wang et al. 2010 ). Finally, junctional adhesion molecule A (JAM-A) is
expressed on CSCs and becomes suppressed during differentiation; being essential
as an adhesion factor for cell maintenance (Lathia et al. 2014 ). JAM-A is a target of
E. Andreopoulou et al.