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they originate from primitive progenitors in the yolk ratio(s), has been positively correlated with the grade
sac and migrate into the CNS during early embryo of glioma malignancy. [68] As another example, patients
development (days 8.5 to 9.5). [55,56] It has also been displaying genetic polymorphisms of the IL-1, IL-10,
clearly demonstrated, using parabiosis (a technique and TNF-α genes are at higher risk for developing
that surgically connects the circulatory system of gastric cancers. [69,70] Studies with human glioma tissues
two organisms) and experimental auto-immune and patient sera indicate Th1, Th2, and Th3 cytokine
encephalomyelitis models, that circulating deregulation as evidenced by increased Th2 associated
monocytes do not invade the CNS unless the CNS cytokines such as IL-10 and the Th3 associated cytokine
is preconditioned with irradiation or the blood-brain TGF-β. This increase is offset by a concomitant decrease
barrier is compromised/damaged. [57-60] Interestingly, in Th1 cytokines such as IL-12, IFN-γ, TNF-α, IL-2, and
a key distinction between “type 1” and “type 2” many of their corresponding receptors. [71,72]
inflammation is that the latter activates bone-marrow
derived macrophage in the CNS and/or brain resident Tumor progression and invasion
microglia. [61,62] Taken altogether, microglia are probably Cancer cells become “self-sufficient” once they
recruited to the glioma microenvironment at all stages have accumulated the proper genetic mutations to
of malignancy, whereas a majority of the macrophages support their own growth. Some of the key findings
accumulate only after insult or blood-brain barrier associated with this stage in disease development
breakdown, when chronic “type 2” inflammation is include independence from external growth factors,
dominant in the glioma microenvironment. the ability to bypass cell senescence, and dysfunctional
apoptotic pathways. In order to develop glioma
Convertibility of macrophage from an M1 to an M2 subtypes, two combinations of genetic mutation may
polarized state is driven by factors produced by the local prevail that involve the mutation of the IDH1 gene
glioma microenvironment. Indeed, secreted or displayed and p53, resulting in astrocytoma formation, or 1p/19q
glioma factors are capable of manipulating macrophage loss of heterozygosity (LOH) leading to formation of
and microglial behavior that favor tumor survival oligoastrocytomas or oligodendrogliomas. [73] Such
and growth. Resting microglia are characterized by a mutations increase the proliferative rate of cancer
ramified morphology; they display extensive branched stem cells, which allows them to grow outside of their
projections that aid in continuous surveillance of the niche. This concept was confirmed in studies using
CNS microenvironment. [63] Glioma cells secrete key an IDH1 mutant model both in vitro and in vivo. [74]
immunomodulatory factors that suppress “type 1” Tumor samples derived from WHO grade II and III
immune activity, such as IL-10, IL-4, IL-6, transforming gliomas were successful in retaining the mutation
growth factor (TGF)-β, and prostaglandin E2. [64-66] The in neurosphere culture. The lower grade gliomas
cytokines IL-10, IL-4, and IL-6 have been shown to proliferate slowly and are difficult to utilize in standard
induce an M2 rounded morphology that is typical in vivo xenograft models.
of activated microglia, whereas the T helper (Th) 3
cytokine, TGF-β, is known to inhibit microglial cell The late stages of “type 2” inflammation primarily
proliferation and the expression of pro-inflammatory consist of extracellular matrix deposition, angiogenesis,
cytokines in vitro. [67] Due to the dominant effect that and tissue remodeling. Once gliomas becomes “self
glioma cells and their secreted factors have on the sufficient”, these late stage processes are aberrantly used
surrounding cells, it is likely that glioma-recruited by the proliferating glioma mass to fuel and sustain
microglia preferentially adopt an M2 phenotype. proliferation. In particular, myeloid derived suppressors
Studies that delineate the interactions between glioma cells are now thought to play a large role in facilitating
cells and macrophages/microglia are still warranted. glioma angiogenesis, neo-vascularization, and
invasion [Figure 1]. Recent studies have shown that the
[75]
Inflammation status temporally may play a pivotal role Tie2-expressing monocyte population is pro-angiogenic,
in cancer development. The “type 1” pro-inflammatory expressing relevant gene transcripts [e.g. matrix
process cannot be sustained in the absence of proper metalloproteinase 9, vascular endothelial growth
stimulation. In brain trauma, “type 1” monocyte factor (VEGF), cyclooxygenase 2, and wingless-type
recruitment from the blood becomes negligible over MMTV integration site family, member 5A] necessary
time, but in low grade gliomas, constant neuronal for angiogenesis and neo-vascularization. [76,77] Some
damage from continuous 2-HG expression may myeloid derived suppressor cells also seem to contribute
prevent the Th1 inflammatory process from subsiding. to the integrity of neo-endothelium of tumor vessels
Eventually both “type 1” and “type 2” immune responses because they express endothelial markers, such as CD31
are both activated leading to chronic inflammation. The and VEGF receptor and can morphologically resemble
strength of “type 2” vs. “type 1” inflammation, which endothelial cells. [78] Microglia also localize near the
is generally reflected by the serum Th2/Th1 cytokine invasive border of the glioma mass at three-fold higher

Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014 69