101also been implicated in the promotion of glioma invasion properties through the
expression of integrin α3 (overexpressed in invading CSCs and perivascular tumor
cells) (Nakada et al. 2013 ). Another mechanism by which integrins (namely α 6 β1)
inhibit pro-apoptotic cascades initiated by tumor necrosis factor (TNF) receptor 1
(TNF-R1), when the cells are attached to laminin, is the induction of the expression
of the cellular FLICE inhibitory protein (cFLIP) (Huang et al. 2012 ). The produc-
tion of laminins and other ECM components within the perivascular glioblastoma
niche is dependent mainly on non-CSCs and endothelial cells (laminin α2, fibronec-
tin and collagen IV) while CSCs express low levels of α2, α3 and α5 laminin chains
(Lathia et al. 2012 ).
Tenascin-C extracellular matrix glycoprotein is another main component of the
ECM of malignant brain neoplasms and is overexpressed in GBM tumors where it
exhibits a strong association with cells in the perivascular compartment (Behrem
et al. 2005 ; Brösicke et al. 2013 ; Lathia et al. 2012 ). Tenascin-C is secreted by tumor
cells (Hirata et al. 2009 ) and has been characterized to be inducing neural progeni-
tor cell migration (Ziu et al. 2006 ), as well as to have anti-anchorage effects on
endothelial cells, visualized by distinct blood vessel characteristics (Xia et al. 2016 ).
Its link with increased motility/migration of GSCs in vitro and in vivo is the anti-
adhesive role it exerts through the modulation of the focal adhesion kinase pathway
(Xia et al. 2016 ). Glioma invasiveness has also been attributed to increased expres-
sion and proteolytic activity of ADAM9 (a disintegrin and metalloproteinase 9)
which involves the mitogen-activated protein kinase 8 pathway (Sarkar et al. 2015 ).
Metalloproteinases are logical candidates for regulating invasiveness of tumor cells
since ECM remodeling is a necessary condition; however, two other members of the
ADAM family, ADAM10 and ADAM17 have also been shown to promote self-
renewal of the GSC population (Bulstrode et al. 2012 ).
In addition to the biochemical cues provided by the ECM, mechanotransduction
has been recognized as a pivotal element in cell-ECM interactions, modulating the
tumorigenic phenotype because the rigidity of the microenvironment impacts tumor
cell migration/proliferation properties. As ECM rigidity increases (stiff ECMs),
glioblastoma cells migrate extensively and proliferate rapidly, while the opposite
behavior is observed in soft ECMs. This efficient rigidity-sensing and propulsive
force-generating system of tumor cells involves components of the cytoskeleton like
myosin II (Umesh et al. 2014 ), α-actinins 1 and 4 (Sen et al. 2009 ), linkers to the
ECM such as talin-1 (Sen et al. 2011 ) as well as sophisticated regulation of epider-
mal growth factor receptor signaling (Umesh et al. 2014 ). Surprisingly, CSCs are
generally insensitive to mechanical inputs and don’t present the typical non-motile
phenotype in compliant ECMs as they generate low levels of myosin-dependent
contractile force. This phenomenon is reversed and activation of myosin-dependent
contractility through RhoA GTPase, Rho-associated kinase (ROCK), or myosin
light chain kinase (MLCK) restores stiffness-dependent migration, leading to a less
invasive phenotype and prolonged survival in mice orthotopically implanted with
such CSCs (Wong et al. 2015 ).
6 Being a Neural Stem Cell: A Matter of Character But Defined...