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

1126 Chapter 20: Cancer
alteration
loss of
Apc
activation of
K-Ras
loss of Smad4
and other tumor
suppressors
loss of
p53
other unknown
alterations
normal
epithelium
hyperplastic
epithelium
early
adenoma
intermediate
adenoma
late
adenoma
carcinoma
invasion and
metastasis
acquisition of increased genetic and epigenetic instability
of oncogenes such as Ras. Experiments in mice show that an initial low level of
oncogene activation can give rise to a slowly growing tumor even while p53 is
functional: genes such as Ras are, after all, part of the normal machinery of growth
control, and moderate activation is not stressful for a cell and does not call the p53
protein into play. Progression of a tumor from slow to rapid, malignant growth,
however, involves activation of oncogenes beyond normal physiological limits to
a higher, stressful level. If the p53 protein is present and functional, this should
lead to cell-cycle arrest or death. Only by losing p53 function can the cancer cells
with hyperactive oncogenes survive and progress.
The steps we have just described are only
MBoC6
part
m20.48/20.36
of the picture. It is important to
emphasize that each case of colorectal cancer is different, with its own detailed
combination of mutations, and that even for the mutations that are commonly
shared, the sequence of occurrence may vary. The same is true for cancers in general.
Advances in molecular biology have recently provided the tools to find out
precisely which genes are amplified, deleted, mutated, or misregulated by epigenetic
mechanisms in the tumor cells of any given patient. As we discuss in the
next section, such information promises to become as important for the diagnosis
and treatment of cancer as was the breakthrough of being able to identify microorganisms
for the treatment of infectious diseases.
Figure 20–36 Suggested typical
sequence of genetic changes underlying
the development of a colorectal
carcinoma. This oversimplified diagram
provides a general idea of the way mutation
and tumor development are related.
But many other mutations are generally
involved, and different colon cancers can
progress through different sequences of
mutations (and/or epigenetic changes).
Summary
The molecular analysis of cancer cells reveals two classes of cancer-critical genes:
oncogenes and tumor suppressor genes. A set of these genes becomes altered by a
combination of genetic and epigenetic accidents to drive tumor progression. Many
cancer-critical genes code for components of the social control pathways that regulate
when cells grow, divide, differentiate, or die. In addition, a subclass of tumor
suppressors can be categorized as “genome maintenance genes,” because their normal
role is to help maintain genome integrity.
The inactivation of the p53 pathway, which occurs in nearly all human cancers,
allows genetically damaged cells to escape apoptosis and continue to proliferate.
Inactivation of the Rb pathway also occurs in most human cancers, illustrating how
fundamental each of these pathways is for protecting us against cancer.
The sequencing of cancer cell genomes reveals that—except for the cancers of
childhood—many cancers acquire 10 or so driver mutations over the long course
of tumor progression, along with a considerably larger number of passenger mutations
of no consequence. The same methods reveal how subclones of cells arise and
die out as a tumor ages. Tumors thus contain a heterogeneous mixture of cells,
some—the so-called cancer stem cells—being much more dangerous than others.
We can often correlate the steps of tumor progression with mutations that
activate specific oncogenes and inactivate specific tumor suppressor genes, with
colon cancer providing a good example. But different combinations of mutations
and epigenetic changes are found in different types of cancer, and even in different
patients with the same type of cancer, reflecting the random way in which these
inherited changes arise. Nevertheless, many of the same changes are encountered
repeatedly, suggesting that there are a limited number of ways to breach our
defenses against cancer.