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change (Kerever et al. 2015 ): their numbers are decreased but their size increases
and their composition in heparan sulfate chain is altered; however, FGF2 capture,
one major functional aspect, remains unchanged. The CNS microenvironment is
known to change, especially in terms of its ECM components, in different patho-
logical conditions such as Alzheimer’s and vascular dementia (Lepelletier et al.
2017 ; Rosenberg 2017 ), autism (Mercier et al. 2011 ), as well as after stroke
(Haddock et al. 2007 ). At the same time, accumulating evidence suggests that in
such cases of pathology the behaviour of NSCs changes (Curtis et al. 2007 ; Darsalia
et al. 2005 , 2007 ; Ekonomou et al. 2010 ; Yamashita et al. 2006 ; Zhang et al. 2014 )
and much more intriguingly latent progenitors seem to be activated (Florio et al.
2015 ; Magnusson et al. 2014 ; Sirko et al. 2013 ). These data, in combination with the
exciting finding that adult brain NSCs can be rejuvenated by systemic factors
(Katsimpardi et al. 2014 ; Ruckh et al. 2012 ), support the expectation that, by deci-
phering the cross-talk between aged or disease-affected NSC with their microenvi-
ronment, this will lead to major breakthroughs in regenerative medicine.
Cancer stem cells (CSCs) exhibit tumor initiation potential (Deleyrolle et al.
2011 ; Piccirillo et al. 2012 ). CSCs express markers such as CD133+ (or prominin)
and Nestin and are found in various brain cancers (glioblastoma, medulloblastomas,
ependymomas and oligodendrogliomas) in close proximity with the aberrant tumor
vasculature. Their interaction with endothelial cells seems to be crucial in maintain-
ing the CSC pool (Bao et al. 2006 ; Calabrese et al. 2007 ), while various microenvi-
ronmental factors provide instructive cues that modulate CSC behavior (Lathia
et al. 2011 ) using mechanisms such as cell-to-ECM interactions, growth factor sig-
naling and cell-to-cell communication (Gilbertson and Rich 2007 ).
6.4.2 Glioma/Glioblastoma (GBM)
6.4.2.1 CSCs-ECM Interactions
Significant signaling crosstalk exists between ECM components and membrane
proteins expressed on CSCs and vascular cells, for example between the laminin
family of proteins and their receptors integrins. Integrins αvβ3 and α 6 β1, are
enriched in CSCs located in the perivascular niche and normally in direct contact
with endothelial cells and are essential for their proliferation and self-renewal while
targeting of integrin α6 reduces tumor formation potential (Burgett et al. 2016 ;
Lathia et al. 2010 ). Activation of integrin-mediated phosphoinositide 3-kinase (PI3-
K) survival signaling has also been reported to facilitate glioma cell migration (Joy
et al. 2003 ), while repression of integrin α6 promoter inhibits stemness of glioblas-
toma cells (Ying et al. 2014 ) via reduced expression by Kruppel-like transcription
factor 9 (KLF9). Moreover, the pro-oncogenic activity of integrin α6 stems from its
association with N-cadherin in order to achieve translocation of extracellular signal-
regulated kinase (ERK) to the nucleus (Velpula et al. 2012 ). The ERK pathway has
E. Andreopoulou et al.