Essential Cell Biology 5th edition

Cancer
727
(A)
Figure 20–50 Colorectal cancer often begins with the
inactivation of both copies of the tumor suppressor gene APC,
leading to growth of a polyp. (A) Thousands of small polyps, and
a few much larger ones, are seen in the lining of the colon of a
patient with an inherited APC mutation (whereas individuals
without an APC mutation might have one or two polyps).
Such polyps arise from cells in which both copies of APC are
inactivated. Through additional mutations in other tumor
(B)
1 mm
suppressor genes or proto-oncogenes, some of the larger
polyps will progress to become invasive cancers, unless the
tissue is removed surgically. (B) Cross section of one such polyp;
note the excessive quantities of deeply infolded epithelium,
corresponding to crypts full of abnormal, proliferating cells
(Movie 20.10). (A, courtesy of Kevin Monahan; B, David Litman/
Shutterstock.)
crypts of the gut lining, as described earlier (see Figure 20–39). When APC
function is lost, the pathway is hyperactive and epithelial cells proliferate
to excess, generating a polyp (Figure 20–50). Within this growing mass
of tissue, further driver mutations occur, sometimes resulting in invasive
cancer (Figure 20–51).
ECB5 e20.52/20.53
The effect of mutations in a variety of tumor suppressor genes and protooncogenes,
including those involved in colorectal cancer, is presented in
Table 20−2.
An Understanding of Cancer Cell Biology Opens the
Way to New Treatments
The nature of the defects that promote the survival, proliferation, and
spread of cancer cells makes the development of effective treatment
strategies particularly challenging. Because cancer cells are highly mutable,
they can rapidly evolve resistance to treatments used to exterminate
them. Moreover, because mutations arise randomly, every case of cancer
is likely to have its own unique combination of genes mutated. Even within
an individual patient, tumor cells do not all contain the same genetic
lesions. Thus, no single treatment is likely to work in every patient, or
even for every cancer cell within the same patient. Finally, the fact that
cancers generally are not detected until the primary tumor has reached a
diameter of 1 cm or more—by which time it consists of hundreds of millions
of cells that are already genetically diverse and often have already
begun to metastasize (Figure 20–52)—makes treatment even harder still.
Figure 20–51 A polyp in the epithelial lining of the colon or rectum,
caused by loss of both copies of the APC gene, can progress
to cancer by accumulation of additional driver mutations. The
diagram shows a sequence of random driver mutations that might
underlie a typical case of colorectal cancer. After the initial mutation,
all subsequent driver mutations arise in a single cell that has already
acquired the previous driver mutations. A sequence of events such
as that shown here would usually be spread over 10 to 20 years or
more. Though most colorectal cancers are thought to begin with
the sequential loss or inactivation of both copies of the APC tumor
suppressor gene, the subsequent sequence of driver mutations is quite
variable; indeed, most polyps never progress to cancer.
normal epithelium
excessive proliferation
of the mutant cells
small tumor
large tumor
tumor becomes invasive cancer
metastasis
INACTIVATION OF BOTH
COPIES OF TUMOR
SUPPRESSOR GENE (APC )
ONE COPY OF PROTO-
ONCOGENE (Ras) ACTIVATED
SEQUENTIAL INACTIVATION
OF BOTH COPIES OF ANOTHER
TUMOR SUPPRESSOR GENE
SEQUENTIAL INACTIVATION
OF BOTH COPIES OF A THIRD
TUMOR SUPPRESSOR GENE (p53 )
RAPID ACCUMULATION
OF OTHER DRIVER
MUTATIONS