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Bioinformatics of the Brain

glial precursor cells have potential to give rise to GBM cancer cells. Contin-

ual uncontrolled cell growth and genomic instability of these cells contribute

to the hallmarks of GBM during tumor development. To undergo transfor-

mation into a GBM cancer cell, these cells accumulate various characteristic

genetic alterations influencing cell behavior and metabolism. Activating or

inactivating mutations in cellular cascades such as growth factor signaling,

tumor suppressor pathways (p53, PTEN and retinoblastoma) and telomerase

activity, cyclin-dependent kinases and their inhibitors mediate global modifi-

cations in the cellular network [5]. However, it has been revealed that GBM

has genetic and epigenetic heterogeneity. For example, of 367 GBM patients

analyzed by Ma et al., 62% of GBM tissue samples showed CDKN2A/B muta-

tion and 43% were positive for EGFR mutations [6]. GBM also shows distinct

patterning in DNA methylation within and between tumors [7].

Unlike a healthy brain, this tumor microenvironment is the home for GBM

stem cells which have self-renewal and differentiation capacity, as well as in-

teract with cellular and non-cellular elements of GBM to direct cell behavior,

resist therapy, remodel ECM, invade and suppress immune screening [8, 9].

Within this space, nano-sized lipid bilayer-enclosed structures called cancer-

derived extracellular vesicles are basic links to deliver important factors that

are essential for various stages of GBM. These vesicles contain growth fac-

tors, receptors, RNAs, diverse set of enzymes and other proteins to mediate

expansion of the tumor. After release, activity of the vesicles goes beyond

primary tissue, and they can even leave the extracellular environment of the

primary tumor and travel through biofluids exerting effects in distant regions

(Figure 3.1) [10–13]. These vesicles also alter the immune activity where they

mediate inactivation and death of immune system cells. For example, PDL-1

delivered through extracellular vesicles promote PD-L1—PD1 interaction of

T cells and thereby, driving their inactivation and death. Thus, PDL-1 con-

taining vesicles contribute immunosuppressive niche of GBM [14]. Further,

extracellular vesicles containing TGF-β inactivate T cells so that granzyme

and perforin secretion is inhibited and IFN-γ secretion is prevented [15]. Other

factors include IL-10 and PGE2, as well as cell-cell contact mediated death

through Fas—FasL, PD-L1—PD1 interaction [16, 17].

3.2.1.2

Tissue Resident Cell Landscape of GBM: Neurons, Astro-

cytes, Microglia, and Oligodendrocytes

Neurons in the brain are affected by impaired functioning and these cells are

under dynamic bidirectional interaction with glioma cells. In an example study

of molecular program modification of neurons by GBM, tumor-adjacent brain

tissue neurons were shown to express PD-L1 under IFN-β based control to trig-

ger proliferation arrest and apoptosis of tumor cells in patient tissue sections

and mouse isograft model [18]. Yet, GBM tumor cells adapt an unfavorable

status for neurons. They can secrete sCD44 that links tau hyperphosphoryla-

tion and pathology of neurodegenerative diseases such as Alzheimer’s disease