Tissue Engineered Models of Brain Tumors and Their Applications

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GBM cells [34], MMP-9 to degrade ECM [35], STI-1 in glioma proliferation

and migration [36], IL-1β for stemness and chemo-resistance [37].

Macrophages need to be polarized to M1 and M2 lineages to operate as

anti-tumor and pro-tumor macrophages. This conversion is dictated by, for

example, IFN-γ/LPS/GM-CSF cues for polarization into M1 macrophages

whereas M2 macrophages rely on IL-4/IL-13/M-CSF signaling [38]. In anti-

cancer surveillance strategy of macrophages, oxidative stress prompted by

NO and ROS, and IFN-γ derived from M1 macrophages are directed to kill

GBM cells [39, 40]. This class of macrophages also secretes a wide range of

other cytokines to activate T cells for targeted tumor cell destruction, as M1

macrophage factors of TNF-α, IL-1β, CXCL9, CXCL10, and IL-12 activate

T cells to target tumor cell for destruction [41–43]. In contrast, contributed

by alternative activation of M2 macrophages, TAMs suppress cytotoxic T cell

activity by PD-L1—PD1, and Fas—FasL dependent cell-cell contact as well as

CTLA-4—CD80/86 engagement [31, 44]. Their capability of arginase-1 expres-

sion depletes a critical amino acid, L-arginine, in extracellular space resulting

in impairment of metabolism and co-receptor expression, thus lowered pro-

liferation and function of T cells [45]. In addition to immunosuppression and

invasion, these cells produce considerable amount of factors to push angiogen-

esis of GBM. So far, it has been demonstrated that well-known stimulating

factors such as VEGF, TGF-β, and FGF elicit signals for pericytes and en-

dothelial cells in tumor vascularization [46, 47].

Neutrophils are other member of immune myeloid lineage migrated to the

brain and they communicate with GBM cells and vascular network of brain

through diverse set of soluble factors. Once recruited by GBM, presence of

HGF in tumor microenvironment leads to production of tumor cell-killing NO

from neutrophils. However, neutrophils support tumor invasion by degrading

ECM with elastase [48, 49]. Their accumulation in brain tumors is correlated

with glioma grade and parallel to T cell suppresion and high levels of Arg1,

ROS, and NO by migrating bone-marrow derived neutrophils [50]. Their po-

tential to induce secretion of S1004A protein from CSCs, thereby activation

of epithelial-to-mesenchymal transition and tumor invasion are confirmed in

vivo, as reported by Liang et al., depletion of S1004A and anti-VEGF ther-

apy were shown to be effective against glioma progression [51]. As supporters,

HMGB-1 and neutrophil extracellular traps (NET) are tumor-promoting fac-

tors acting through cancer cell proliferation and invasion. Tumor infiltrating

neutrophil-derived HMGB-1 binds to RAGE of glioma cells and stimulates

NF-κβ transcription pathway factor and, leads to secretion of IL-8 that results

in poor prognosis [52]. S100A8 and 9, VEGF and MMP9 are other proteins

expressed by neutrophils for ECM degradation, endothelial cell activation and

angiogenesis in tumors [53, 54].

As a part of innate immune system, natural killer (NK) cells attack the

brain tumor through perforin and granzyme creating a lytic pore and acti-

vating caspases. Pro-inflammatory cytokines such as TNF-α and IFN-γ of

NK cells attract and activate antigen-presenting cells and T cells. Yet as