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7.2 Discovery of Cancer Cells Expressing Stem Cell Surface
Markers
A stochastic model in which all cancer cells possessed similar proliferative capabil-
ity was predicted to explain tumor progression. Cancers were therefore thought to
arise upon spontaneous mutations that occur within terminally differentiated
somatic cells leading to aberrant cellular proliferation (Hanahan and Weinberg
2011 ; Dalerba et al. 2007 ). Teratomas, which are benign masses arising from aber-
rantly proliferating undifferentiated stem cells were thought to occur only in rare
cases due to genetic and developmental defects within the germline cell lineages.
Researchers later discovered a subpopulation within acute myeloid leukemia (AML)
patient samples associated with normal hematopoietic stem cells by sorting for
expression of cell surface markers (Lapidot et al. 1994 ). Clonogenic assays showed
that this small subset of cancer cells expressing normal stem markers, now termed
cancer stem cells (CSCs), could give rise to de novo leukemia, histologically similar
to parental disease, when engrafted in bone marrow of immunocompromised mice
(Lapidot et al. 1994 ). Using ectopic xenograft assays, it was determined that CD38+/
CD34- immunophenotype were able to initiate de novo leukemia in immunocom-
promised mice (Lapidot et al. 1994 ). Subsequently, studies sorting for the presence
normal stem cell markers in populations of cancer cells found similar CSC in solid
cancers in locations such as the breast, liver, colon, prostrate, pancreas, skin (mela-
noma) and brain (Singh et al. 2003 ; Fang et al. 2005 , 2010 ; Zhu et al. 2010 ;
Tomuleasa et al. 2010 ).
The brain had long been thought to have limited differentiation and regenerative
capabilities but the discovery of neural stem cells (NSCs) (prior to the discovery of
CSCs) within distinct niches in the subventricular zone (SVZ) of the forebrain lat-
eral ventricles and the subgranular zone (SGZ) in the dentate gyrus of the hippo-
campus indicated that neurogenesis within the brain could possibly occur throughout
adult life (Riquelme et al. 2008 ; Vescovi et al. 2006 ; Eriksson et al. 1998 ). The dis-
covery of CSCs in leukemia and other solid cancers led to studies aimed at discover-
ing similar such cancer cells within tumors of the central nervous system. The initial
discovery of neurosphere forming undifferentiated stem cells within human GBM
biopsy samples (GSCs) and the identification of CD133+ as a marker for this cel-
lular subpopulation within those samples alerted researchers to the possibility of
cell populations within GBMs which might have greater differentiation capability
than other cells within tumors (Ignatova et al. 2002 ; Uchida et al. 2000 ; Singh et al.
2004b). Xenograft studies found that the CD133+ subset of GBM cells could give
rise to histologically identical orthotopic GBMs in immunocompromised rodents.
Later studies also showed that these GSCs could be differentiated into cells showing
decreased differentiation and proliferation capabilities (Laks et al. 2009 ; Kang et al.
2014 ; Bradshaw et al. 2016 ). These findings gave rise to a hierarchic model to pre-
dict tumor progression, in which undifferentiated cancer cells expressing stem cell
surface markers were considered at the top of the hierarchy and cancer cells show-
ing reduced differentiation capabilities, such as transiently amplifying progenitor
A. Sattiraju et al.