132
and its cellular receptor integrin α 6 β1 in GBM cells has been reported to promote
tumor progression (Huang et al. 2012 ). Laminin is also a critical component in
adherent GSC cultures, upon which GSCs tend to form tumorspheres. Heparin sul-
phate binds to basic Fibroblast Growth Factor (bFGF) and stimulates GBM cell
growth and prevents radiation induced cell death (Bao et al. 2006a; Folkman et al.
1988 ). Binding of GBM cells to ECM components allows for intracellular signal
transduction through formation of multimeric complexes termed focal adhesions
with other proteins such as focal adhesion kinase (FAK) (Fidoamore et al. 2016 ;
Gilmore and Romer 1996 ).
Integrin play a vital role in the interactions of GBM cells with components of the
ECM and vascular cells such as endothelial cells and pericytes. Integrin α6 is highly
expressed in NSCs where it heterodimerizes with integrinβ1 and integrin β4 and
binds to ECM protein laminin. Through its binding to laminin, integrin α 6 β1 regu-
lates self-renewal and differentiation by favoring adhesion to ventricular zone
(Fortunel et al. 2003 ). GBM cells that overexpress integrin α6 were reported to
show self-renewal and ability to differentiate into CNS lineage indicating that inte-
grin α6 expression confers stem-like cellular state (Lathia et al. 2010 ). Integrin β 1
plays an important role in perivascular niche where it promotes GBM invasion and
functions together with CXCR4 to regulate critical stem cell pathways such as SHH,
Wnt, and Notch. Integrin α3 is overexpressed on invasive GBM and on GBM cells
in close proximity to endothelial cells and is thought to regulate invasiveness of
GSCs through ERK1/2 pathway (Nakada et al. 2013 ). Overexpression of integrin
αvβ5 and integrin αvβ3 is associated with heightened invasiveness of GBMs and
overexpression of integrin αvβ8 is associated with a more infiltrative phenotype in
GBMs. Paracrine factors such as TGF-β1 and TGF-β2 are associated with an
increase in the integrins αvβ3, αvβ5 and αvβ8 and thus result in aggressive GBMs
(Fidoamore et al. 2016 ). Interaction of vitronectin (VN) with integrins αvβ3 and
αvβ5 has been reported to enhance expression of Bcl-2 and Bcl-XL and confer che-
moresistance at invasive ends of GBM. Overexpression of integrins αvβ3, αvβ5 and
β1 along with an increase in synthesis of basement membrane components such as
fibronectin and matrigel have been reported to confer radio-resistence to GBM cells
(Uhm et al. 1999 ).
Cadherins stimulate intracellular signaling upon intercellular adhesion between
GBM cells and regulators of their cell fate such as cdc42, protein kinase C (PKC),
β-catenin and Numb. N-cadherin plays a vital role in the NSC niche where it main-
tains the stem cell differentiation state while overexpression of E-cadherin in GBM
samples is associated with poor patient outcomes. E-cadherin expressing CD133+
GSCs have also been reported to transdifferentiate into endothelial cells. Cadherin
11 plays a vital role by enhancing migration of GBM cells in tumors. Expression of
cadherins is regulated by interleukin 8 (IL-8) and transcriptional activators such as
FoxP2, FoxP4, Twist and Snail (Fidoamore et al. 2016 ; Brooks et al. 2013 ). Tenascin
C has been reported to be highly expressed after radiation therapy in GBMs and its
expression is correlated with poor patient survival as it promotes tumor cell growth
and preserves differentiation state of GSCs (Leins et al. 2003 ; Mannino and
Chalmers 2011 ) (Fig. 7.2).
A. Sattiraju et al.