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 AS A MICROEVOLUTIONARY PROCESS
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Figure 20–9 Clonal evolution. In this schematic diagram, a tumor develops
through repeated rounds of mutation and proliferation, giving rise eventually
to a clone of fully malignant cancer cells. At each step, a single cell
undergoes a mutation that either enhances cell proliferation or decreases
cell death, so that its progeny become the dominant clone in the tumor.
Proliferation of each clone hastens the occurrence of the next step of tumor
progression by increasing the size of the cell population that is at risk of
undergoing an additional mutation. The final step depicted here is invasion
through the basement membrane, an initial step in metastasis. In reality, there
are more than the three steps shown here, and a combination of genetic and
epigenetic changes are involved. Not shown here is the fact that, over time, a
variety of competing subclones will often arise in a tumor. As we will discuss
later, this heterogeneity complicates cancer therapies (see Figure 20–30).
Human Cancer Cells Are Genetically Unstable
Most human cancer cells accumulate genetic changes at an abnormally rapid
rate and are said to be genetically unstable. The extent of this instability and its
molecular origins differ from cancer to cancer and from patient to patient, as we
shall discuss in a later section. The basic phenomenon was evident even before
modern molecular analyses. For example, the cells of many cancers show grossly
abnormal sets of chromosomes, with duplications, deletions, and translocations
that are visible at mitosis (Figure 20–10). When the cells are maintained in culture,
these patterns of chromosomal disruption can often be seen to evolve rapidly
and in a seemingly haphazard way. And for many years, pathologists have
used an abnormal appearance of the cell nucleus to identify and classify cancer
cells in tumor biopsies; in particular, cancer cells can contain an unusually large
amount of heterochromatin—a condensed form of interphase chromatin that
silences genes (see pp. 194–195). This suggested that epigenetic changes of chromatin
structure can also contribute to the cancer cell phenotype, as recently confirmed
by molecular analysis.
The genetic instability observed in cancer cells can arise from defects in the
ability to repair DNA damage or to correct replication errors of various kinds.
These alterations lead to changes in DNA sequence and produce rearrangements
such as DNA translocations and duplications. Also common are defects in chromosome
segregation during mitosis, which provide another possible source of
chromosome instability and changes in karyotype.
From an evolutionary perspective, none of this should be a surprise: anything
that increases the probability of random changes in gene function heritable from
one cell generation to the next—and that is not too deleterious—is likely to speed
the evolution of a clone of cells toward malignancy, thereby causing this property
to be selected for during tumor progression.
accidental production
of mutant cell
cell with
2 mutations
cell with
3 mutations
epithelial cells
growing on
basal lamina
CELL
PROLIFERATION
CELL
PROLIFERATION
DANGEROUS CELL
PROLIFERATION
MBoC6 m20.11/20.09
(A)
(B)
Figure 20–10 Chromosomes from a
breast tumor displaying abnormalities
in structure and number. Chromosomes
were prepared from a breast tumor cell in
metaphase, spread on a glass slide, and
stained with (A) a general DNA stain or
(B) a combination of fluorescently labeled
DNA molecules that color each normal
human chromosome differently (see Figure
4–10). The staining (displayed in false color)
shows multiple translocations, including a
doubly translocated chromosome (white
arrow) that is made up of two pieces of
chromosome 8 (green-brown) and a piece
of chromosome 17 (purple). The karyotype
also contains 48 chromosomes, instead
of the normal 46. (Courtesy of Joanne
Davidson and Paul Edwards.)