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study has demonstrated the presence of GSCs near chemotherapeutic agents. [17] Temozolomide (TMZ)
blood vessels, consistent with the perivascular niche treatment, which could eliminate O6-methylguanine-
for NSCs. [10,11] Alternatively, Li et al. [12] demonstrated DNA methyltransferase-negative cells, increased the
that GSCs could also be found in regions of necrosis, stem population. [22] Increased expression of drug
which are hypoxic, suggesting that there may be more transporters, such as ATP-binding cassette (ABC)
than one niche. Hypoxia promotes the self-renewal transporters, could lead to chemotherapeutic agents
capability of both the stem cell and nonstem cell being pumped out of tumor cells and may be another
populations, and also promotes the conversion of mechanism of chemo-resistance. Recent studies
nonstem cells into stem cells by up-regulating the have found that the expression of ABC transporters
expression of important stem cell factors, [13] indicating is increased in stem cells. [23] Therefore, focusing
that this niche may be important for GSCs. Therapies on the connection between GSCs and their niche
that target cytokines, such as hypoxia-inducible factor- may help to elucidate the mechanisms behind the
1α (HIF-1α) and HIF-2α, or cells in the niche, such as treatment-resistant phenotype of GSCs, which
glia cells and endothelial cells, may, therefore, show may lead to solutions that reduce the resistance of
promise. gliomas to therapy and improve clinical outcome.
This information may also be useful in the pursuit
Glioma stem cells and resistance to therapy of effective therapeutic strategies for the treatment of
Surgical resection, radiation, and chemotherapy radiation-associated injuries.
are still the mainstay treatments for gliomas and
are associated with a clear improvement in overall Cell sorting and culture
survival in patients with high-grade gliomas. Several methods may be used in order to obtain purified
However, recurrence of the tumor is common GSCs for study. In some studies, fluorescence-activated
following conventional therapy. Antiangiogenic cell sorting and magnetic activated cell sorting have
therapy against vascular endothelial growth factor been used to separate GSCs from other cell types. [12,24]
is another frequently used therapeutic treatment, Glioma cell lines and clinical samples have also been
but drug resistance is common. [14] The mechanisms used to isolate and culture GSCs. [25,26] However, there
of resistance are not understood in complete detail is currently no standard definition of what constitutes
and may be multi-factorial. The proposal that GSCs a GSC. Specific markers for identifying GSCs are,
are a prerequisite for tumor formation suggests that therefore, required. The current definition of GSCs
chemo- and radio-resistant GSCs are the main cause is based on their capacity for self-renewal, long-term
of recurrence. [15,16] Liu et al. [17] found that CD133 cells proliferation, and tumor formation in vivo. The ideal
+
were resistant to chemotherapeutic agents, whereas marker, therefore, is a molecule that is specifically
CD133 cells sorted from the same primary glioma expressed on GSCs and functionally associated with
−
cultures were not. Furthermore, Bao et al. GSC maintenance.
[7]
determined that ionizing radiation treatment enriched
the CD133 population in human gliomas. Although CD133 has been widely used as a marker for GSC sorting.
+
CD133 does not identify all GSCs, these data However, NSCs also express CD133, which limits its
suggest that GSCs play a key role in resistance to utility and reliability as a target. Some studies have also
traditional therapies. The mechanism for resistance suggested that CD133 cells have the capability to act as
−
is complicated. Bao et al. demonstrated that GSCs. [13] Moreover, CD133 glioma cells can give rise to
[7]
−
CD133 cells contribute to glioma radio-resistance via CD133 GSCs. Other surface molecules such as CD15
+
+
[13]
preferential activation of DNA damage checkpoints, (SSEA-1), [27] A2B5, [28,29] and L1CAM [30] have been used
and that their resistance could be partially reversed as markers but are not widely accepted. Interestingly,
by inhibitors of Chk1 and Chk2. Other researchers both CD133 A2B5 and CD133 A2B5 cells have been
+
−
−
+
demonstrated that the bone morphogenetic proteins shown to exhibit characteristics of GSCs. [31] Therefore,
and cannabinoids inhibit the tumorigenic potential of these markers may only label specific sub-populations
GSCs and promote their differentiation. [18] Radiation of GSCs. In recent times, one group exploited the
treatment may expand the GSC population, enhance intrinsic auto-fluorescence properties and distinctive
the aggressiveness of tumors, and induce expression morphology of a subpopulation of cells (FL1 ) in
+
of GSC marker proteins, such as CD133 and nestin, order to isolate them from human gliomas. FL1 cells
+
as well as proteins involved in self-renewal, such as are capable of self-renewal in vitro, tumorigenesis
Notch2 and Sox2. [19] The GSC niche may enhance in vivo, and preferentially express stem cell genes, but
the radio-resistance of GSCs as well. [20] Besides expression of FL1 did not correlate with the expression
their relative radio-resistance, GSCs can express of other proposed GSC markers. This finding deserves
[32]
high levels of multiple genes associated with drug special attention as it may provide a new way to identify
resistance [21] and show significant resistance to GSCs.
52 Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014