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

MBoC6 n20.290/20.28
CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
1117
Cancers of Specialized Tissues Use Many Different Routes to
Target the Common Core Pathways of Cancer
Mutations in core components of the machinery that regulates cell growth, division,
and survival, such as Rb, Ras, PTEN, or p53, are not the only way to pervert
the control of these processes. Specialized tissues depend on a variety of pathways,
as discussed in Chapter 15, to relay environmental signals to the core control
machinery, and each pathway lays the cells open to subversion in a different
set of ways. Thus, in different cancers, we can find examples of driver mutations
in practically all the major signaling pathways through which cells communicate
during development and tissue maintenance (discussed in Chapters 21 and 22).
In glioblastoma, for example, most patients have mutations in one or other of
a set of cell-surface receptor tyrosine kinases, especially the EGF receptor mentioned
earlier (linking into the Ras/PI3K pathway), suggesting that the cells from
which the cancer originates are normally controlled by this route. The cells of the
prostate gland, on the other hand, respond to the androgen hormone testosterone,
and in prostate cancer, components of the androgen receptor signaling pathway
(a variety of nuclear hormone receptor signaling; see Chapter 15) are often
mutated. In the normal gut lining, Wnt signaling is critical, and Wnt pathway
mutations are present in most colorectal cancers. Pancreatic cancers generally
have mutations in the transforming growth factor-β (TGFβ) signaling pathway.
Activating mutations in the Notch pathway are present in more than 50% of T cell
acute lymphocytic leukemias, and so on.
Cells are generally regulated by several different types of external signals that
must act in combination, representing a “fail-safe” control mechanism that protects
the organism as a whole from cancer. These signals are different in different
tissues. As expected, therefore, the corresponding cancers often have mutations
in several signaling pathways concurrently. This is true of the examples we have
just listed, which commonly have mutations in other signaling pathways in addition
to the ones that we have singled out.
Studies Using Mice Help to Define the Functions of Cancer-Critical
Genes
The ultimate test of a gene’s role in cancer has to come from investigations in the
intact, mature organism. The most favored organism for such studies, apart from
humans themselves, is the mouse. To explore the function of a candidate oncogene
or tumor suppressor gene, one can make a transgenic mouse that overexpresses
it or a knockout mouse that lacks it. Using the techniques described in
Chapter 8, one can engineer mice in which the misexpression or deletion of the
gene is restricted to a specific set of cells, or in which expression of the gene can
be switched on at will at a chosen point in time, or both, to see whether and how
tumors develop. Moreover, to follow the growth of tumors from day to day in the
living organism, the cells of interest can be genetically marked and made visible
by expression of a fluorescent or luminescent reporter (Figure 20–28). In these
ways, one can begin to clarify the part that each cancer-critical gene plays in cancer
initiation or progression.
67 103 144 266 372
age in days
metastases
Figure 20–28 Monitoring tumor growth
and metastasis in a mouse with a
luminescent reporter. A mouse was
genetically engineered in a way that allows
both copies of its PTEN tumor suppressor
gene to be inactivated in the prostate
gland, simultaneously with the prostatespecific
activation of a gene engineered
to produce the enzyme luciferase (derived
from fireflies). After an injection of luciferin
(the substrate molecule for luciferase) into
the mouse’s bloodstream, the cells in the
prostate emit light and can be detected
by their bioluminescense in a live mouse,
as seen in the 67-day-old animal at the
left. Cells lacking the PTEN phosphatase
enzyme contain elevated amounts of the
Akt activator, PI(3,4,5)P 3 , and this causes
the prostate cells to proliferate abnormally,
progressing over time to form a cancer. In
this way, the process of metastasis could
be followed in the same animal over the
course of a year. The light intensity in these
experiments is proportional to the number
of prostate-cell descendants, increasing
from light blue to green, to yellow, to red
in this representation. (Adapted from
C.-P. Liao et al., Cancer Res. 67:7525–
7533, 2007.)