Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

3.1 The Cancer Stem Cell Hypothesis Introduction
required, at limiting dilutions, to seed new tumours. The pioneering studies in
leukemia and later solid tumours showed that it is possible to use cell surface
marker profiles to isolate cancer cell subpopulations that are enriched for or
depleted of cancer stem cells. Subsequent reports showed that, after implanta-
tion in vivo, cancer stem cell-enriched populations generate tumours that are
no longer enriched for cancer stem cells, implying that the cancer cells within
a single tumour are naturally found in multiple states of differentiation with
distinct tumour-seeding properties. The stemming possibility of bidirectional
interconversion between cancer stem cell and non-cancer stem cell populations
does not undermine the cancer stem cell hypothesis, since the two populations
always retain their distinct identities and they can be distinguished phenotyp-
ically and functionally at any moment (Fig 3.1) [182].
One of the emerging caveats of the cancer stem cell hypothesis is the actual
frequency of cancer stem cells. In normal tissues, somatic stem cells are inher-
ently rare, and most of this type of data in cancer is derived from xenograft
experiments, in which the frequency of human cancer stem cells is determined
upon transplantation into a mouse environment. Differences between human
and mouse stromal and support cells, cytokines as well as distinct levels of
immunological function in different immunodeficient recipient mouse strains,
have led to conflicting frequencies of cancer stem cells ranging between 1% and
25%. This discrepancy has highlighted that the stem cell properties of cancer
stem cells are inherent but might also be the result of the interaction with the
environmental milieu [393]. Thus, as suggested by recent findings, the number
of cancer stem cells in a tumour may be a function of the cell type of origin,
stromal 36 microenvironment, accumulated somatic mutations and stage of ma-
lignant progression reached by the tumour. In fact, an early report indicated
that the proportion of leukemia stem cells varies up to 500-fold between patient
samples. More recent reports have suggested that relatively undifferentiated
tumours at the histopathological level may contain higher proportions of cancer
stem cells than their more differentiated counterparts. Furthermore, the num-
ber of cancer stem cells may be different between tumour subtypes that arise
from a single tissue, indicating that the cancer stem cells may be as numerous
as the non-cancer stem cells in certain subtypes. However, the cancer stem cell
hypothesis can be adapted to state that cancer cells can exist in at least two
alternative phenotypic states with different tumour-seeding potentials, with-
36 Connective tissue supporting the parenchymal cells of an organ.
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