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(Heddleston et al. 2011 ). GSCs have also recently been shown to transdifferentiate
into endothelial cells (Heddleston et al. 2011 ; Ricci-Vitiani et al. 2010 ; Wang et al.
2010b). These data indicate that CD133 could be considered as a biomarker of
GSCs and provides survival advantages to tumors. However, evidence suggests that
additional markers could more precisely identify GSC populations due their drivers
and high plasticity.
Alternate cell surface markers such as integrin α6, SSEA-1, A2B5 and CD44
could also be considered to enrich for GSC population (Ogden et al. 2008 ). Integrin
α6 high cells have been reported to be more tumorigenic than integrin α6 low cells.
Integrin α6 co-segregates with CD133 but integrin α6 positive cells are enriched for
neurosphere formation regardless of enrichment in CD133 expression. Knockdown
of integrin α6 impedes neurosphere formation and tumor development in xenografts
indicating that integrin α6 is probably expressed on a broader pool of GSCs (Lathia
et al. 2010 ). SSEA-1 (stage specific embryonic antigen-1) is thought to be secreted
by neural stem cells to modulate Wnt signaling and has been shown to be expressed
on CD133+ tumors. SSEA-1+ GBM cells also show greater tumorigenicity when
compared to SSEA-1- GBM cells (Son et al. 2009 ). A2B5+ GBM cells have also
been shown to be highly tumorigenic compared to A2B5- GBM cells. This corrobo-
rates the fact that A2B5 has been shown to co-segregate with CD133 in flow cytom-
etry studies (Ogden et al. 2008 ). But, similar to integrin α6, A2B5+/CD133- GBM
cells showed tumor initiating capability in xenograft studies. This indicates that
A2B5 could be used to enrich a broader pool of GSCs. Side population using
Hoechst 33,342 was also shown to as a cell surface marker independent technique
to enrich for GSCs. However, conflicting reports about the tumorigenic capability of
isolated cells as well as viability issues after exposure to the dye have yet to be
addressed (Bleau et al. 2009 ). Intracellular stem markers such as Olig2, Musashi,
Bmi and Sox2 could also be used to verify enriched GSC populations (Bao et al.
2006a). These studies indicate that more than one biomarker may potentially have
to be used in order to segregate a GSC population. Additionally, the set of biomark-
ers used to efficiently segregate GSCs from one patient’s GBM may not efficiently
segregate the entire pool of GSCs from another patient’s GBM due to the highly
heterogeneous nature of the disease.
7.2.2 Glioblastoma Cell of Origin
The stochastic and hierarchic models not only predict gross steps that occur in the
process of tumor progression but also indicate possible cells of origin (COIs) in a
variety of cancers. The identification and isolation of COIs in GBM and other can-
cers could not only indicate which of the two predicted models of tumor progression
might be accurate but could also shed light on the emergence of CSCs and their role
in tumors maintenance, which eventually could lead to identification of better tar-
gets for cancer therapy.
Currently, there are two lines of thought regarding COIs of cancers, one that
assumes that somatic differentiated cancer cells undergo de-differentiation and
A. Sattiraju et al.