Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
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(A)
stem
cell
stem cell
transit
amplifying cells
(B)
mixed cell population in tumor
stem cell propagates
new tumor
transit amplifying
cells eventually die
(the outer epithelial layer of the skin), the lining of the digestive and reproductive
tracts, and the bone marrow, where blood cells are generated (see Chapter 22).
In almost all these tissues, renewal depends on the presence of stem cells, which
divide to give rise to terminally differentiated cells, which do not divide. This creates
a mixture of cells that are genetically identical and closely related by lineage,
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but are in different states of differentiation. Many tumors seem likewise to consist
of cells in varied states of differentiation, with different capacities for cell division
and self-renewal.
To see the implications, it is helpful to consider how normal stem-cell systems
operate. When a normal stem cell divides, each daughter cell has a choice—it
can remain a stem cell, or it can commit to a pathway leading to differentiation.
A stem-cell daughter remains in place to generate more cells in the future. A
committed daughter typically undergoes some rounds of cell proliferation (as a
so-called transit amplifying cell) but then stops dividing, terminally differentiates,
and eventually is discarded and replaced (it may die by apoptosis, with recycling
of its materials, or be shed from the body). On average, the two fates—stem cell or
differentiating cell—normally occur with equal probability, so that half the daughters
of stem-cell divisions take the one path and half take the other. In a healthy
body, feedback controls regulate the process, adjusting this balance of cell-fate
choices to correct for any departure from the proper cell population numbers.
Thus, the number of stem cells remains approximately constant, and the terminally
differentiated cells are continually replaced at a steady rate. Because of the
divisions undergone by the transit amplifying cells, the stem cells may be vastly
outnumbered by the cells that are committed to terminal differentiation and have
lost the capacity for self-renewal. But the stem cells, though few and far between
and often relatively slowly dividing, carry the whole responsibility for maintenance
of the tissue in the long term.
Some cancers seem to be organized in a similar way: they consist of rare cancer
stem cells capable of dividing indefinitely, together with much larger numbers
of dividing transit amplifying cells that are derived from the cancer stem cells
but have a limited capacity for self-renewal (Figure 20–32). These non-stem cells
appear to constitute the great majority of the cell population in some tumors.
Figure 20–32 Cancer stem cells can be
responsible for tumor growth and yet
remain only a small part of the tumorcell
population. (A) How stem
cells produce transit amplifying cells.
(B) How a small proportion of cancer stem
cells can maintain a tumor. Suppose, for
example, that each daughter of a cancer
stem cell has a probability slightly greater
than 50% of retaining stem-cell potential
and a probability slightly less than 50% of
becoming a transit amplifying cell that is
committed to a program of cell divisions
that stops after 10 division cycles. While
the number of cancer stem cells will
increase slowly but steadily to give a
growing tumor, the non-stem cells that they
give rise to will always outnumber the stem
cells by a large factor—in this example, by
a factor of about 1000. (If the cell-divisioncycle
and survival times for the two classes
of cells are equal.)
The Cancer Stem-Cell Phenomenon Adds to the Difficulty of
Curing Cancer
Evidence for the cancer stem-cell phenomenon comes chiefly from experiments
in which individual cells from a cancer are tested for their ability to give rise to fresh
tumors: a standard assay is to implant the cells into an immunodeficient mouse
(Figure 20–33). It has been known for half a century that there is usually only a
small chance—typically much less than 1%—that a tumor cell chosen at random
and tested in this way will generate a new tumor. This by itself does not prove that