103miR-145 (negative regulator), which is downregulated in CSCs (Alvarado et al.
2016 ). High JAM-A/low miR-145 expression signature has significant predictive
value and presents clinical relevance as it indicates poor patient survival (Alvarado
et al. 2016 ).
6.4.2.3 Diffusible Factors
A key factor of the glioma micro-environment in initiating tumorigenesis by GSCs
is Transforming Growth Factor-beta (TGFβ). TGFβ induces the self-renewal
capacity of GSCs through the Smad-dependent induction of leukemia inhibitory
factor (LIF) and the subsequent activation of the JAK-STAT pathway (Peñuelas
et al. 2009 ). Moreover, TGFβ activity is mediated by the ID family of helix-loop-
helix proteins (Anido et al. 2010 ). Expression levels of IDs are higher in tumor cells
and ECs of higher grade glial neoplasms correlate with proliferation and angiogen-
esis patterns (Vandeputte et al. 2002 ). ID4 transforms astrocytes into a stem-cell like
state through Notch signaling (Jeon et al. 2008 ) and ID3 promotes GSCs features in
astrocytes (Jin et al. 2011 ). In addition, pAKT-pSmad5 signaling-driven ID3 induc-
tion by activation of EGF signaling along with the subsequent production of ID3-
regulated cytokines (GRO1, interleukin-6 (IL-6) and interleukin-8 (IL-8),
enhances tumor formation, expansion and heterogeneity (Jin et al. 2011 ). Finally,
CSCs are able to protect themselves from endogenous BMPs via the expression of
the BMP antagonist Gremlin1. Gremlin1 blocks the pro-differentiation effects of
BMPs via the p21WAF1/CIP1 complex and overexpression of Gremlin1 in non-
CSCs decreases their endogenous BMP signaling to promote stem-like features
(Yan et al. 2014 ).
6.4.2.4 Hypoxia
As with NSCs during development, in the adult brain hypoxic micro-environmental
conditions maintain and expand the GSC phenotype (Bar et al. 2010 ; Heddleston
et al. 2009 ; Li et al. 2009 ; Seidel et al. 2010 ; Soeda et al. 2009 ). HIFs have been
shown to facilitate GSC survival and self-renewal (Li et al. 2009 ; Soeda et al. 2009 ).
HIF2α induces VEGF expression exclusively in the stem cell subpopulation (Li
et al. 2009 ; Seidel et al. 2010 ), whereas HIF1α transcriptionally regulates the VEGF
promoter in GSCs and non-GSCs cells (Li et al. 2009 ) and represses Neuropilin-2
(NRP2) in non-GSC cells, increasing paracrine VEGF-induced EC function and
inhibiting the potent anti-tumorigenic activity of semaphorin 3F (SEMA3F) (Coma
et al. 2011 ). By stabilizing the intracellular domain of Notch, HIF1α synergizes
with Notch and drives CSC maintenance (Qiang et al. 2012 ). Targeting HIF iso-
forms results in anti-proliferative and anti-tumorigenic effects while reducing cell
migration/invasion in vitro and in vivo (Li et al. 2009 ; Méndez et al. 2010 ; Seidel
et al. 2010 ).
6 Being a Neural Stem Cell: A Matter of Character But Defined...