Tissue Engineered Models of Brain Tumors and Their Applications

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between pre-clinical and clinical applications, but not well-documented as in

murine models [191–194].

In recent years, GBM models are recreated to improve and facilitate the

drug discovery, screening, and patient specific therapeutic strategies. In these

studies, cell source (immortalized or patient-derived), cellular and environ-

mental heterogeneity, communication, variation of omics information, resis-

tance mechanisms as well as BBB characteristics have been the central interest

to achieve significant advancement in clinical translation. In one of the exam-

ple studies, Han et al. reported the emergence of DOX-resistant U87 cell phe-

notype in a GBM microfluidic device. After DOX treatment, GBM cells that

repopulated the empty chambers led to emergence of DOX-resistant cells with

an IC50 value 30-fold larger than wild-type cells. In these resistant cells, mu-

tations in genes of DOX transport, metabolism, and signaling were reported

as major contributors for DOX resistance [195].

More readily, first step to 3D has been linked to (hetero)spheroids and

organoids models, and these approaches provided influential results for drug

screening. These models can replicate collection of intratumoral cell type and

cycle dynamics, as GBM solid tumor is constituted by proliferating and quies-

cent subpopulations that are linked to tumor recurrence after treatment. As it

is previously reported, both quiescent and proliferative GBM cells have poten-

tial to form spheres but size is measured to be small in quiescent ones. In this

model, quiescent GBM cell organoids were more resistant to temozolomide

treatment and radiotherapy with distinct gene expression profile such as in-

creased expression of ECM proteins of FN1, laminins, collagens, and tenascin

C [154]. Cellular heterogeneity in terms of tumor cell subpopulations further

extents the range of drug response. In one of such studies, Sivakumar et al.

arranged spheroid models with four types of GBM cells with mainly distinct

EGFR mutations to address effects of tumor population. During culture, drug

treatments reshaped the spheroid composition highlighting the dominant con-

tribution of genetic heterogeneity of tumor cells [196].

In chemotherapy, although main target is the tumor cells for the sake of

prognosis, all remaining patient cells are also exposed to deleterious effects of

the drugs and may present the potential side effects. For this reason, espe-

cially 3D models are great to analyze overall toxicity risks associated with the

treatment. For instance, in GBM patient heterospheroids of tumor cells and

iPSC-derived neural progenitor cells, selective induction of tumor cell apop-

tosis by temozolomide can be modeled [197]. However, chemotherapy drugs

used for GBM patients often exert toxic effects on astrocytes and, 2D systems

have been limited to uncover such effects. As an innovative approach for the

establishment of clinical relevance, the micro-pillar based chips devised with

GBM or astrocytes allowed spheroid formation and were promising to screen

accuracy of various chemotherapeutic drugs [198]. Besides, as a probable role

to cure GBM, selective targeting tumor cells and immune system cells can be

advantageous. To illustrate this effect, in a recent study, targeting GBM cells

and TAMs by PD-1 and CSF1R dual inhibition was shown to be effective