82

Bioinformatics of the Brain

CD44 interaction with hyaluronic acid also triggers expression of certain path-

ways implicated in GBM migration and survival [97]. Another significant brain

ECM protein group is chondroitin sulfate proteoglycans (CSPGs) that reveal

robust changes in function and level in healthy and diseased state [98]. With

increased but uneven expression in GBM, collagen IV contributes disrupted

basement membrane in tissue sections and allows migration of tumor cells as

previously demonstrated [99, 100]. Moreover, laminin-411 is highly expressed

in GBM patients resulting in poor survival and high risk of recurrence of tumor

by driving invasion and potentially supporting angiogenesis [101]. In GBM,

fibronectin interactions direct tumor growth via cell migration, differentia-

tion, and contributes tumor angiogenesis [102]. Additionally, investigation of

the mechanism of action of elastin in brain tumors indicate that GBM cells

express tropoelastin (soluble form of elastin) and a cell surface receptor called

elastin binding protein to adhere elastin and to invade [103].

3.2.3

Vasculature in Brain and GBM

A dynamic network of vessels supplies blood to meet the metabolic demands of

the brain. However, transport processes are far more strictly controlled due to

the presence of blood-brain barrier (BBB) which is one of the prominent rea-

sons for the failure of drug delivery into the brain (Figure 3.2). As an interface

between blood and brain tissue, BBB is present on different types of vessels

providing a unique pathway for cellular activity. Function of the barrier is not

limited to be a physical barrier, but it is also essential for ion homeostasis,

neurotransmitter and growth factor level control, prevention of leakage into

the brain and protection against neurotoxins. However, modifications in this

interface are observed as clinical signature events in GBM [104–106].

The microenvironmental background of the BBB in capillaries is shaped

by multiple factors. A continuous layer of endothelial cells is held together

thoroughly by mainly cell-cell junctions and attached to extracellular space

with various cell surface receptors. This blood-contacting layer is coated by

the basement membrane and is supported by pericytes and astrocytes [107,

108]. The junctions and their components as active mediators of endothelial

layer integrity are summarized in Figure 3.2. These junctions mediate cell-

cell connection, transfer, transendothelial leukocyte migration, and signaling.

Although BBB dictates the flow of substances between the blood and the

brain, each molecule has a distinct pathway through endothelium to route

themselves in and out of the brain [109–111].

BBB undergoes transformation into the blood-tumor barrier in GBM.

Blood-tumor barrier features are heterogeneous and, reduced junctions,

nonuniform pericyte localization, astrocyte end-feet displacement result in per-

meable vessels thereby advancing fluid pressure and accessibility into the brain

[112]. In brain tumors, the profile of the endothelial cells differs within the tu-

mor and from the surrounding tissue. In these distinct regions, endothelial

transporters and carriers are differentially expressed in the endothelial cells