Tissue Engineered Models of Brain Tumors and Their Applications

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involves application of such technologies in preclinics and clinics pointing out

the promise of dimensional and other manipulations for the future of GBM

treatment and research.

3.4.1

Tumor Biology

In vitro GBM models play a pivotal role in decoding the tumor considering

microenvironment, communication and heterogeneity, and omics knowledge.

This dynamic environment dictates permissive conditions for various natural

processes. Eventually, not only the cellularity of tumor and blood vessel net-

work change but also an escape route to other possible habitats is established

to harbor a metastatic niche. In spheroid and organoid systems, the estab-

lishment of hypoxic core, proliferation and packaging zones [155, 168], GSC

interaction with MSCs [146], differentiation [184], surfaceome and endocytome

[185] were researched and also, they are combined with scaffold-based and mi-

crofluidic systems. In these approaches, ECM analogs with various scaffolds

provide invaluable aspects of tumor biology.

In general, physical properties of substrates/scaffolds have been reported

to control diverse mechanisms. To delineate role of these properties on malig-

nancy, Pedron et al. encapsulated U87 cells in gelatin hydrogels and manip-

ulated stiffness with monomer concentration and degree of functionalization.

They observed that U87 tumor cell proliferation and spreading were promoted

in stiff gelatin gels with greater steric hindrance. Moreover, thicker and more

crosslinked gels interfered with diffusivity largely and cells in such gels, ex-

pressed elevated levels of HIF1 and VEGF due to hypoxia [186]. Likewise,

changes in stiffness guide migration and morphological switches [187]. Charac-

teristics of network microstructure such as porosity, spatial organization, and

degradability are among the other main factors dictating invasion of cells, as

more ordered networks are also linked to spreading and migratory phenotype.

For this purpose, a recent comparison between a collagen gel and hyaluronic

acid gel provided that single tumor cells remained rounded with a tendency

to form aggregates in compact hyaluronic gels with curled fibers whereas in

porous collagen gels, cells were more isolated, elongated with a larger motil-

ity. Spheroid invasion assays further confirmed superiority of the ordering in

networks [163]. Furthermore, degradation of scaffolds is crucial for especially

pore sizes smaller than cellular dimensions, as cells in natural ECM pave their

migration and trajectory by mainly enzymatic degradation of the ECM. Tran-

sition into a biomimetic system generally follows the same rule for migration

and invasion of healthy or tumor cells. To represent this mechanism in a pre-

clinical model, Hill et al. designed tunable PEG hydrogels and degradability

was a major determinant of invasion supported by adhesion ligand, RGDS.

Non-degradable gels were reported to be not infiltrated by GBM tumor cells

whereas invasion increased throughout the culture period for degradable ones

being higher with adhesive hydrogels [164]. Presentation of cell adhesion sites

is equally important for a scaffold to sustain migration of encapsulated cells.