Essential Cell Biology 5th edition

726 CHAPTER 20 Cell Communities: Tissues, Stem Cells, and Cancer
Figure 20–49 A small number of key
regulatory pathways are perturbed in
almost all human cancers. These pathways
regulate cell proliferation, cell growth, cell
survival, and the cell’s response to DNA
damage or stress.
ALTERATIONS IN
CELL PROLIFERATION
ALTERATIONS IN DNA
DAMAGE RESPONSE
ALTERATIONS IN
CELL GROWTH
CANCER
ALTERATIONS IN
CELL SURVIVAL
all human cancers (Figure 20–49). In any given patient, only a single gene
tends to be mutated in each pathway, but not always the same gene: it
is the under- or overactivity of the pathway as a whole that matters for
cancer development, not the way in which this malfunction is achieved.
Because the same fundamental control systems are the targets of mutation
in so wide a variety of cancers, it seems that their misregulation
must be crucial to most cancers’ success.
ECB5 e20.51-20.52
Colorectal Cancer Illustrates How Loss of a Tumor
Suppressor Gene Can Lead to Cancer
Colorectal cancer provides one well-studied example of how a tumor
suppressor gene can be identified and its role in tumor growth determined.
Colorectal cancer arises from the epithelium lining the colon and
rectum; most cases are seen in old people and do not have any discernible
hereditary cause. A small proportion of cases, however, occurs in
families that are exceptionally prone to the disease and show an unusually
early onset. In one set of such “predisposed” families, the affected
individuals develop colorectal cancer in early adult life, and the onset of
their disease is foreshadowed by the development of hundreds or thousands
of little tumors, called polyps, in the epithelial lining of the colon
and rectum.
By studying these families, investigators traced the development of the
polyps to a deletion or inactivation of a tumor suppressor gene called
APC—for Adenomatous Polyposis Coli. (Note that the protein encoded by
this gene is different from the anaphase-promoting complex, abbreviated
APC/C, discussed in Chapter 18.) Affected individuals inherit one mutant
copy of the gene and one normal copy. Although one normal gene copy
is enough for normal cell behavior, all the cells of these individuals are
only one mutational step away from total loss of the gene’s function (as
compared to two steps away for a person who inherits two normal copies
of the gene). The individual tumors arise from cells that have undergone
a somatic mutation that inactivates the remaining good copy of APC (see
Figure 20–46B). Not surprisingly, the disease strikes these individuals at
an earlier age than it does in individuals with two good copies of APC.
But what about the great majority of colorectal cancer patients, who do
not have the hereditary condition or any significant family history of cancer?
When their tumors are analyzed, it turns out that in more than 60%
of cases, although both copies of APC are present in the adjacent normal
tissue, the tumor cells themselves have lost or inactivated both copies of
this gene (see Figure 20-48B).
All these findings clearly identify APC as a tumor suppressor gene and,
knowing its sequence and mutant phenotype, one can begin to decipher
how its loss helps to initiate the development of cancer. As explained
in How We Know (pp. 730–731), the APC gene was found to encode an
inhibitory protein that normally restricts the activation of the Wnt signaling
pathway, which is involved in stimulating cell proliferation in the