Biomedical Engineering Reference
In-Depth Information
is inducible. The basic concept of differentiation therapy is that specific identifi-
able cell signaling pathways maintain ''stemness'' in cancer stem cells. If the
stemness signaling pathways that regulate cancer stem cells can be modified,
then the cancer stem cells should progress, becoming cancer transit-amplifying
cells. As cancer transit-amplifying cells, they would be susceptible to other
forms of therapy (Kelly et al., 2007; Furth and Kahn, 1937; Sell, 2007a; Hill
and Perris, 2007; Till and McCulloch, 1961; Becker et al., 1963; Till et al., 1964;
Makino and Kano, 1955).
2.4.1 Leukemia
Differentiation therapy has been most successfully applied to human leukemia.
Leukemia is a malignant cancer of the blood and lymphoid system. It is
manifested by a massive increase in immature white blood cells in the circula-
tion. The presence of so many white blood cells in the blood causes the color of
the blood to change from red to creamy or white. The term leukemia means
white blood (leukos - white; haima - blood). Because of the replacement of the
normal immune and inflammatory cells with leukemic cells, patients with
leukemia usually die, because they are unable to fight off infections. Leukemia
is caused by a failure of the cells in the white blood cell lineage to mature into
functional cells (maturation arrest).
The Leukemic Stem Cell
The first definitive demonstration of tissue-specific stem cells for the hemato-
poietic system was in 1961 (Till and McCulloch, 1961); small numbers of
normal mouse bone marrow cells were transplanted by intravenous injection
into heavily irradiated mice. After 10-14 days, the spleens of these recipient
mice contained nodules of maturing and mature blood cells. Thus, stem cells of
the bone marrow could give rise to hematopoietic colonies in this system in
which each colony was shown to be a single clone (Becker et al., 1963; Till et al.,
1964). Even before these elegant observations, Furth and Kahn in 1937 demon-
strated that leukemia of mice could be transplanted via a single cell (Furth and
Kahn, 1937), and Makino and Kano (1955) concluded that leukemia arises
from a progenitor or stem cell. More recently, with the use of the nude immu-
nodeficient mouse as a recipient for human cancer cells, an approach first
reported in 1969 (Rygaard and Povlsen, 1969), the transplantability of human
leukemic cells has been examined. Of special interest was the finding that only 1
in 250,000 or so leukemic cells is able to transfer acute myeloid leukemia (AML)
to a SCID mouse (Sutherland et al., 1996; Bonnet and Dick, 1997; Lapidot
et al., 1994). This observation indicates that leukemia cannot be transplanted by
means of the tumor transit-amplifying cells, but only by means of the true
tumor stem cells. When a pathologist looks at the cells in the blood or bone
marrow of a patient with AML, essentially all of the leukemic cells appear to be
blasts. This suggests that all of the AML cells are dividing transit-amplifying
