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GBM TYPES AND STAGES IN DISEASE was revealed. Cells encoding the mutant IDH1 protein
PROGRESSION were found to convert, in an irreversible reaction,
α-ketoglutarate to 2-hydroxyglutarate (2-HG). [19] The
GBM is classified as one of two types: primary or function of the accumulation of 2-HG and its role
secondary GBM. Primary GBM arises as the de novo in disease progression is not yet fully elucidated.
high grade disease that has no discernible stages of The fundamental role of 2-HG has been difficult to
progression. Secondary GBM, on the other hand, arises assign partly because its role is unlike conventional
as low grade and over time progresses to a higher-grade onco-metabolites characterized thus far. Rather than
of malignancy. Therefore it is extremely difficult - if promoting disease progression by conferring itself with
not impossible - to analyze the changes that arise a proliferative or selective advantage, 2-HG initiates
in a step-wise manner for primary GBM, while the development of the cancer stem cell niche within the
progression of secondary GBM can be closely followed. frontal lobe. Thus, the onco-metabolite 2-HG is the first
However, recent genomic analysis of primary resected example demonstrating that although the derivation of
GBM tissue has allowed for a second dimension of cancer is mono-cellular in nature at initiation, much
their grouping by gene expression/mutations patterns: like tumor promotion and progression, complicated
neural, pro-neural, classical, and mesenchymal. [15] heterogeneous interactions involving multiple cell types
occurs. The cellular interplay also offers an explanation
Contemporary theory links the phenotypic to the challenges associated with establishing a tumor
characteristics observed in the tumor microenvironment model containing solely the IDH1 mutation both in vivo
to each of three stages of glioma pathology: initiation, and in vitro. [20] This cancer stem cell niche may in
promotion and progression. [16] A defect in the switch turn provide the mutant IDH1 stem-like cell with the
for wound repair may play a major role in glioma necessary factors to promote self-renewal, further
development because it leads to “type 2” chronic genetic mutations, and ultimately disease progression.
inflammation that fails to shut off and this may drive Indeed, previous studies in patients suffering from
gliomagenesis. Further, “type 2” chronic inflammation, the genetic disorder known as D-2-hydroxyglutaric
which is propagated indefinitely in the tumor aciduria, where the accumulation of 2-HG is observed,
microenvironment, may be critical in triggering tumor show ROS-mediated neural excito-toxicity upon NMDA
initiation. The effect of chronic inflammation that receptor chronic potentiation by 2-HG. [21,22] The neural
develops in the tumor microenvironment is far reaching excito-toxicity fueled by the IDH1 mut stem-like cell
beyond the initiating effects, and it may also drive the may initiate a neural-inflammatory cycle of wound
second stage of disease, glioma promotion. The third repair ultimately leading to pro-creation of a cancer
and last stage of the disease, glioma progression, is stem cell niche that promotes glioma formation and
a stage of the disease that loops back adding to the immune evasion. This niche provides the cancer stem
intensity of the underlying inflammation. cell with growth factors to sustain proliferation and
an environment that promotes the emergence of more
The initiating event genetic mutations. Indeed, a connection between
Embracing the cell of origin model, the theoretical excitotoxicity and inflammation has been proposed to
consideration of the inflammatory-initiating event be linked by interleukin-1β. [23]
beginning with a specific mutation in the cancer
stem cell may occur either through oncogene Tumor promotion
over-expression/stimulation or production of an Inflammation is the first line of defense in response
inflammatory onco-metabolite. A traumatic event at a to tissue injury and/or infection. Pro-inflammatory
specific site in the brain may activate all the necessary cytokines such as tumor necrosis factor (TNF)-α,
signal transduction pathways to initiate inflammation. Interleukin (IL)-1β, and IL-6 are synthesized to
The site of injury could be a source of micro-damage initiate the inflammatory cascade. [24] IL-1 has been
induced by chronic stress, depression, or some other shown to be a key mediator in the proliferation of
factor extrinsic to the host. [17] “reactive astrocytes”. [25] Next, either of two types of
inflammatory processes may be activated depending
As another consideration, the source of the micro-damage on the stimulus. In the presence of microbial infection
and neural-degeneration may be the cancer stem cell or necrotic cell death classical “type 1” inflammation
itself. Recently, a novel genetic mutation encoding the ensues, characterized by the appearance of activated
isocitrate dehydrogenase 1 (IDH1) protein known to be T helper (Th) 1 lymphocytes. [26] In the presence of
present in a large number of low-grade to secondary GBM parasites, allergens, or phosphatidylserine positive
tumors has been identified as one of the possible first early apoptotic cells the Th2 inflammatory cascade is
events in disease initiation. [18] Subsequently, following activated. Interestingly, Th2 inflammation is closely
the identification of this mutated oncogene, its function related to wound repair. Indeed, the principal mode of

Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014 67