Essential Cell Biology 5th edition

Cancer
721
Figure 20−43 Cancer incidence increases dramatically with age.
The number of newly diagnosed cases of cancer of the colon in
women in England and Wales in one year is plotted as a function of
age at diagnosis. Colon cancer, like most human cancers, is caused by
the accumulation of multiple mutations. Because cells are continually
experiencing accidental changes to their DNA—which accumulate and
are passed on to progeny cells when the mutated cells divide—the
chance that a cell will become cancerous increases greatly with age.
(Data from C. Muir et al., Cancer Incidence in Five Continents, Vol. V.
Lyon: International Agency for Research on Cancer, 1987.)
10—and, as we will see, they have to affect the right type of gene. These
mutations do not all occur at once but occur sequentially, usually over a
period of many years.
Cancer, therefore, is most often a disease of old age, because it takes a
long time for an individual clone of cells—those derived from a common
founder—to accumulate a sufficient number of cancer-critical mutations
(Figure 20−43). Many human cancer cells are able to speed up this
acquisition of mutations because they are also genetically unstable. This
genetic instability results from mutations that interfere with the accurate
replication and maintenance of the genome and thereby increase the
rate at which mutations accumulate. Sometimes, the increased mutation
rate may result from a defect in one of the many proteins needed to repair
damaged DNA or to correct errors in DNA replication. Sometimes, there
may be a defect in the cell-cycle checkpoint mechanisms that normally
prevent a cell with damaged DNA from attempting to divide before the
damage has been fully repaired (discussed in Chapter 18). Sometimes,
there may be a fault in the machinery of mitosis, which can lead to chromosomal
damage, loss, or gain; an abnormal chromosome number can
then, itself, increase mitotic errors. These potential sources of genetic
instability are summarized in Table 20–1.
Genetic instability can produce chromosome breaks and rearrangements—even
complete chromosome duplications. Such gross abnormalities
can often be seen in a karyotype of the cancer cell (Figure 20–44).
cancer incidence rate per 100,000
180
160
140
120
100
80
60
40
20
0
10 20 30 40 50 60 70 80
age (years)
ECB4 eQ20.16/20.46
Cancer Cells Evolve, Acquiring an Increasing
Competitive Advantage
The mutations that lead to cancer do not cripple the mutant cells. On the
contrary, they give these cells a competitive advantage over their neighbors.
It is this advantage enjoyed by the mutant cells that leads to disaster
for the organism as a whole. As an initial population of mutant cells
grows, it slowly evolves: new chance mutations occur, some of which are
favored by natural selection because they enhance cell proliferation, cell
survival, or both. This process of random mutation followed by selection
culminates in the genesis of cancer cells that run riot within the
population of cells that form the body, upsetting its regular structure
(Figure 20–45).
Certain environmental or lifestyle factors, such as obesity, may further
favor the development of cancer by altering the selection pressures that
operate in tissues. A glut of circulating nutrients, or abnormal increases
in hormones, survival factors, mitogens, or growth factors, for example,
may help cells with dangerous mutations to survive, grow, and proliferate.
Eventually, cells emerge that have all the abnormalities required for
full-blown cancer.
To be successful, a cancer cell must acquire a whole range of abnormal
properties—a collection of subversive behaviors. A proliferating
TABLE 20−1 A VARIETY OF
FACTORS CAN CONTRIBUTE TO
GENETIC INSTABILITY
Defects in DNA replication
Defects in DNA repair
Defects in cell-cycle checkpoint
mechanisms
Mistakes in mitosis
Abnormal chromosome numbers