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

CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
1119
normal
cells
cancer
founder cell
driver mutations
(A)
CELLULAR ENVIRONMENTAL CONSTRAINTS
cell death
1 2 or more 3 or more 4 or more
time
Euclidean distance
0
1
2
normal stromal cells
3
4
5
cells with greatly amplified K-Ras
1 20 40 60 80 100
cell number
(B)
normal
mammary
epithelial
development
first
driver
mutation
appearance of most
recent common ancestor
further driver mutations
proliferative clones that
have become extinct
final rate-limiting
driver mutation
embryo time breast tumor
(C)
diagnosed
number
of cells
subclones. From the shared abnormalities, one could deduce that their last common
ancestor—the presumed founder of the cancer—was already very different
from a normal cell, but that the first split between branches occurred early, when
the tumor was small. This was followed by a large amount of additional change
within each branch. A hint of the future could be seen in the smallest of the three
major subclones: its cells were distinguished by a massive amplification of a Ras
oncogene. Given more time, perhaps they would have out-competed the other
cancer cells and taken over the whole tumor.
Similar results have been obtained with other cancers. Clearly, cancer cells are
constantly mutating, multiplying, competing, evolving, MBoC6 n20.310/20.30
and diversifying as they
exploit new ecological niches and react to the treatments that are used against
them (Figure 20–30C). Diversification accelerates as they metastasize and colonize
new territories, where they encounter new selection pressures. The longer
the evolutionary process continues, the harder it becomes to catch them all in the
same net and kill them.
Figure 20–30 How cancers progress
as a series of subclones. (A) Schematic
illustration of the pattern of mutation and
natural selection in a clone of tumor cells.
(B) A family tree of cancer cells sampled
from different regions of a single breast
tumor, showing how the cells have evolved
and diversified from a common ancestor,
the cancer founder cell. The genome of
each of the indicated 100 cells from a
human breast tumor was sequenced to
produce an evolutionary tree. About half
of these cells were normal cells from the
stroma (blue cells). The red cells have
greatly amplified their K-Ras gene.
Note that many subclones appear to have
died out, including the one that contained
the founder cells for the three subclones
that survive.
(C) A depiction of how driver mutations
are thought to cause cancer progression
over long periods of time, before producing
a large enough clone of proliferating cells to
be detected as a tumor. The data indicate
that driver mutations occur only rarely in
a background of long-lived subclones of
cells that continually accumulate passenger
mutations without gaining a growth
advantage. (A, adapted from M. Greaves,
Semin. Cancer Biol. 20:65–70, 2010;
B, adapted from N. Navin et al., Nature
472:90–94, 2011; C, adapted from
S. Nik-Zainal et al., Cell 149:994–1007,
2012.)
The Changes in Tumor Cells That Lead to Metastasis Are Still
Largely a Mystery
Perhaps the most significant gap in our understanding of cancer concerns invasiveness
and metastasis. For a start, it is not clear exactly what new properties a
cancer cell must acquire to become metastatic. In some cases, it is possible that
invasion and metastasis require no further genetic changes beyond those needed
to violate the normal controls on cell growth, cell division, and cell death. On the
other hand, it may be that, for some cancers, metastasis requires a large number
of additional mutations and epigenetic changes. Clues are coming from comparisons
of the genomes of cells of primary tumors with the cells of metastases that
they have spawned. The results appear complex and variable from one cancer to
another. Nevertheless, some general principles have emerged.
As we discussed earlier, it is helpful to distinguish three phases of tumor progression
required for a carcinoma to metastasize (see Figure 20–16). First, the cells