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Bioinformatics of the Brain

to GBM [19]. They interfere with insulin signaling pathway creating synapse

loss and mitochondrial disruption of neurons [20]. Meanwhile, tumor cells can

secrete laminin that is modified by neurons and support neuron survival [21].

Most importantly, in glioma, tumor cells can be coupled with the electrical

environment. Within this network, glioma cells advance hyperexcitability of

neurons and, AMPA-receptor and potassium current-based tumor growth [22].

Astrocytes are fundamental to the normal brain, yet in early tumor stages

of a homeostatically imbalanced brain, astrocytes attempt to protect healthy

cells and deplete excess glutamate so that neurons will be able to survive. In

later stages, they promote tumors with reduced glutamate uptake, increased

TGF-β and MMP levels in the environment. This dual role of astrocytes de-

pends on the exchange of extracellular vesicles constituted with the cargo of

mRNAs for c-myc, cyclin-D3, RP, OXPHOS, and glycolysis to transformed as-

trocytes for metabolic reprogramming, and various proteins and other nucleic

acids [23, 24]. Astrocytes also criple immune system cells to adapt immuno-

suppressive niche, as they manipulate pro-inflammatory cytokine profile into

anti-inflammatory one, cause natural killer cell dysfunction as well as abolish T

cell and macrophage function [25, 26]. Moreover, after polarization, microglia

in the brain support tumor growth with several signaling cascades directed

by cell-cell contact and soluble factors. For example, mTOR signaling-based

STAT3 phosphorylation is a clue for the secretion of anti-inflammatory cy-

tokines such as IL-6 and IL-10 [27].

Under conditions where GBM begins to invade white matter, on the bor-

der regions, oligodendrocytes progenitor cells accumulate. Especially, myeli-

nated axons are significant, as they are the tracks for GBM cells to escape

from therapeutics [28]. These cells are useful tools for GBM cell invasion, as

PDGF-C signaling of oligodendrocytes progenitor cells in the brain releases

proangiogenic factors such as IGFBP-1 and MMP9 to open BBB and activate

endothelial cells [29].

3.2.1.3

Immune Microenvironmental Components in GBM

Among cellular components in GBM, tumor associated macrophages/microglia

(TAMs) are one of the most abundant cells, as they usually constitute up to

50% of the cells in tumor tissue. Sources of TAMs are macrophages infiltrat-

ing into the brain and tissue-resident microglia. In healthy brain, microglia

are considered as effector macrophages of the CNS. However, in brain tumors,

critical roles of TAM rely on immunosuppression, support of invasion, prolifer-

ation as well as angiogenesis. Soluble factors and certain enzymes are secreted

by glioma cells to recruit TAMs to the area of tumor mass to promote growth

(Figure 3.1) [30, 31]. TAMs secrete various factors to boost GBM invasive-

ness such as EGF to increase proliferation and motility [32], TIMP-1, lL-6,

and CCL5 induced by GBM cell extracellular vesicles for ECM degradation

and tumor growth [33], CCL8 for invasion and stem-cell like characteristic of