226
Cancer Stem Cells
demonstrated that as few as one hundred
CD44
+
CD24
/
low
Lineage
cells were able
to form tumors, while tens of thousands of
cancer cells from outside this population
failed to form tumors in NOD/SCID mice,
as shown in Fig. 1. These tumorigenic
cells could be serially passaged, and each
time cells within this population generated
new
tumors
containing
additional
CD44
+
CD24
/
low
Lineage
tumorigenic
cells. Additionally, phenotypically mixed
populations of nontumorigenic cancer
cells
were
produced
that
composed
the
bulk
of
the
tumor.
Importantly,
their phenotypic distribution resembled
that of the original tumor. These data
demonstrate the presence of a hierarchy of
cells within a breast cancer tumor in which
only a fraction of the cells have the ability
to proliferate extensively, while other cells
have only a limited proliferative potential,
suggesting that the tumorigenic cells can
both self-renew as well as differentiate.
The phenotype of the tumorigenic breast
cancer cells may be similar to normal
breast stem or progenitor cells, since early
multipotent
epithelial
progenitor
cells
have been reported to express both ESA
and CD44. While this would be consistent
with the similarities observed between
normal HSCs and AML tumor-initiating
cells, de±nitive proof will depend upon
the characterization of the differentiation
hierarchy of breast tissue.
The CD44
+
CD24
/
low
Lineage
tumori-
genic
breast
cancer
cells
and
the
CD34
+
CD38
leukemia-initiating
cells
share with normal stem cells the ability
to proliferate extensively, as well as to
give rise to cells of diverse phenotypes
with reduced developmental or prolifera-
tive potential. The extensive proliferative
potential of tumorigenic cancer cells con-
trasts with the bulk of the cancer cells,
which lack the ability to form detectable
tumors and form smaller colonies
in vitro
.
Thus, both tumorigenic breast cancer cells
and leukemia-initiating cells from most
tumors appear to exhibit the properties of
cancer stem cells. However, before these
cells can de±nitively be called cancer stem
cells, new assays will be necessary to
demonstrate that a single transplanted cell
gives rise to all of the diverse populations
of cancer cells within a tumor.
Cancer stem cells share many key prop-
erties with normal stem cells, including
the ability to self-renew. In addition,
normal stem cells are likely to be the
cells in which oncogenic mutations ac-
cumulate and in some cases may be
the target cells for neoplastic transfor-
mation. Appreciating the implications of
the discovery of cancer stem cells for the
diagnosis and treatment of cancer conse-
quently depends upon understanding the
key properties of stem cells, the genetic
regulation of these properties, and how
cells can be targeted for neoplastic trans-
formation.
3
Properties of Normal Stem Cells
3.1
The Hematopoietic Stem Cell and its
Properties
The accessibility of the hematopoietic sys-
tem to study has made the HSC the
most studied and best understood so-
matic stem cell population; consequently,
it serves as a model for stem cells from
other tissues. Hematopoiesis is a tightly
regulated process in which a pool of
HSCs, through a series of divisions and
immature progenitors, eventually gives
rise to the mature lymphohematopoietic
system consisting of the formed blood
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