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has investigated the presence and role of inflammatory from highly immature [33,34] to terminally differentiated
cells in the SVZ of brain tumor patients. cells. [35,36] This has further suggested that a stem
cell hierarchy might operate in HGG and might be
It has been shown that inflammatory processes involving responsible for its highly heterogeneous phenotype. [31]
interleukin-6 (IL-6) are initiated after neonatal CNS after
injury and that both IL-6 and another member of the same However, more recent studies have pointed out that
cytokine family, i.e. leukemia inhibitory factor, contribute the capacity of tumor cells to mimic the functional
to the expansion of neural stem and progenitor cells in properties of stem cells is a “plastic” process that can
the SVZ after injury [22,23] by activating the JAK/STAT be influenced by extrinsic factors (for instance, a more
[24]
pathway. Despite the high expression of IL-6 in HGG permissive microenvironment characterized by high
and its promotion of tumor growth and invasion, the immunosuppression [37,38] ) or by instrinsic factors (for
[26]
[25]
role of this cytokine is not fully understood. In a mouse instance, transcription factor that can induce a stem
model of astrocytomas with inactivation of the IL-6 gene cell transcriptional program in tumor cells ), thus
[39]
locus, tumor formation is suppressed suggesting that suggesting that cancer stem cells are the result of an
IL-6 is required for glioma growth. Additional studies aberrant program of cell plasticity. [40]
[27]
are required to elucidate the functional role of IL-6 in the
SVZ of HGG patients. This might extend our knowledge THE SVZ AS AN ONCOGENIC NICHE
about its role in promoting malignancy and sustaining
neural stem cell self-renewal. The importance of the SVZ as a potential oncogenic
niche stems from an initial study in the 40s’ suggesting
THE SVZ AND THE CANCER STEM CELL that brain tumors with ventricular walls contact
HYPOTHESIS might originate from the embryonic rests present in
the SVZ. This was followed by studies in the 60s’
[41]
The idea that cancers derive from stem cells is not showing that mitosis occurs in the sub-ependymal
entirely new. In recent years evidence supporting this layer of rodent and primate brain [5,42] and in the 70s’
[28]
concept has been provided by several works on non-solid with the intraventricular injections of oncogenic
and solid cancers. Intriguingly, the concept of a stem cell viruses. [43,44] More recently, other studies took advantage
hierarchy inside a tumor found confirmation in several of the development of genetically-modified viruses and
pathologies, from leukaemia to solid cancers (i.e. breast, animal models. Interestingly, in mice it was initially
brain, colon cancers) [29,30] with the hematopoietic system shown that undifferentiated (precursor) cells can be
providing the best example in both chronic myeloid more easily transformed when compared to cells that
[31]
leukaemia and multiple myeloma. are terminally differentiated, [45,46] thus corroborating
the hypothesis that neural stem/precursor cells might
However, the initial evidence for the existence of cancer represent the target of malignant transformation. In
stem cells in several tumors has been followed by the addition to the above findings, a subsequent study
consistent observation that these cells hijack functional comparing cultures of astrocytes vs. neurosphere
properties of normal stem cells. In particular, it has been precursor cells has shown that dedifferentiation of
thought that virtually all cancer cell lines available can astrocytes (promoted by EGFR activation) makes
be turned into cancer stem cells by changing the growth these cells susceptible to malignant transformation
medium and by exposing them to mitogenic stimuli. More similarly to neural stem cells, by combining loss of
importantly, the functional similarities with normal critical tumor suppressors, i.e. p16Ink4a/p19Arf. [47]
stem cells has also led to speculate that if cancer cells
resemble stem cell features then the tumor itself might Following the characterization of the adult brain SVZ
originate from the malignant transformation of normal as stem cell niche in rodents and humans [8,12,48] and the
stem cells of that particular tissue, therefore cancer stem identification of “cancer stem cells”, animal models
[49]
cells might represent the tumor “cell of origin”. However, have been extensively developed in order to understand
“cancer stem cell” and “cell of origin” represent two if the SVZ can be a source of brain tumors. [31]
different concepts that are often confused and used
[32]
interchangeably. In HGG, it has been shown that neurogenic regions are
susceptible to malignant transformation, in particular
In HGG, there is evidence that the tumor derives from following stereotactic infusion of growth factors, such
stem/precursor cells in genetically-engineered animal as PDGF, in the SVZ. [50,51] Similarly, using genetically-
models of the disease (see next section “The SVZ as an engineered mouse models, it has also been demostrated
oncogenic niche”). Histological studies on HGG patients that HGG can be driven by tumor suppressor
revealed a mixture of cell morphologies including inactivation in neural stem/progenitor cells [52,53] and
virtually all the spectrum of differentiating cells, that a subpopulation of stem-like/Nestin(+ve) cells is

22 Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016