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

1122 Chapter 20: Cancer
the tumor cells are heterogeneous: like seeds scattered on difficult ground, each
of them may have only a small chance of finding a spot where it can survive and
grow. Modern technologies for sorting cells have shown, however, that in some
cancers at least, the rate of success in founding new tumors is even lower than it
would otherwise be because the cancer cells are heterogeneous in their state of
differentiation, and only a small subset of them—the cancer stem cells—have the
special properties needed for tumor propagation. For example, in several types
of cancer, including breast cancers and leukemias, one can fractionate the tumor
cells using monoclonal antibodies that recognize a particular cell-surface marker
that is present on the normal stem cells in the tissue of origin of the cancer. The
purified cancer cells expressing this marker are found to have a greatly enhanced
ability to found new tumors. And the new tumors consist of mixtures of cells that
express the marker and cells that do not, all generated from the same founder cell
that expressed the marker.
Experiments with breast cancer cells have revealed that, instead of following a
rigid program from stem cell to transit amplifying cell to terminally differentiated
cell, these cancer cells can randomly switch to and fro—with a certain low transition
probability—between different states of differentiation that express different
molecular markers. In one state, they behave like stem cells, dividing slowly but
capable of founding new tumors; in other states, they behave like transit amplifying
cells, dividing rapidly but unable to found new tumors in a standard transplant
assay. But a single cell in any of these states—given time in culture, or a congenial
environment in the body—will give rise to a mixed population that includes all the
other states as well.
The cancer stem-cell phenomenon, whatever its basis, implies that even when
the tumor cells are genetically similar, they are phenotypically diverse. A treatment
that wipes out those in one state is likely to allow survival of others that
remain a danger. Radiotherapy or a cytotoxic drug, for example, may selectively
kill off the rapidly dividing cells, reducing the tumor volume to almost nothing,
and yet spare a few slowly dividing cells that go on to resurrect the disease. This
greatly adds to the difficulty of cancer therapy, and it is part of the reason why
treatments that seem at first to succeed often end in relapse and disappointment.
Figure 20–33 An immunodeficient
mouse, as used in transplantation
assays to test human cancer cells for
their ability to found new tumors. This
MBoC6 n20.251/20.33
nude mouse has a mutation that blocks
development of the thymus and, as a
side effect, robs it of hair. Because it has
practically no T cells, it tolerates grafts of
cells even from other species. (Courtesy of
Harlan Sprague Dawley.)
Colorectal Cancers Evolve Slowly Via a Succession of Visible
Changes
At the beginning of this chapter, we saw that most cancers develop gradually from
a single aberrant cell, progressing from benign to malignant tumors by the accumulation
of a number of independent genetic and epigenetic changes. We have
discussed what some of these changes are in molecular terms and seen how they
contribute to cancerous behavior. We now examine one of the common human
cancers more closely, using it to illustrate and enlarge upon some of the general
principles and molecular mechanisms we have introduced. We take colorectal
cancer as our example.
Colorectal cancers arise from the epithelium lining the colon (the large intestine)
and rectum (the terminal segment of the gut). The organization of this tissue
is broadly similar to that of the small intestine, discussed in detail in Chapter 22
(pp. 1217–1221). For both the small and large intestine, the epithelium is renewed
at an extraordinarily rapid rate, taking about a week to completely replace most of
the epithelial sheet. In both regions, the renewal depends on stem cells that lie in
deep pockets of the epithelium, called intestinal crypts. The signals that maintain
the stem cells and control the normal organization and renewal of the epithelium
are beginning to be quite well understood, as explained in Chapter 22. Mutations
that disrupt these signals begin the process of tumor progression for most colorectal
cancers (Movie 20.6).
Colorectal cancers are common, currently causing nearly 60,000 deaths a year
in the United States, or about 10% of total deaths from cancer. Like most cancers,
they are not usually diagnosed until late in life (90% occur after the age of
55). However, routine examination of normal adults with a colonoscope (a fiber