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 AS A MICROEVOLUTIONARY PROCESS
1099
differentiated tissue
oxidative
phosphorylation
NET PRODUCTS:
glucose
ENERGY, CO 2 , H 2 O
(A)
GLYCOLYSIS
pyruvate
lactate
proliferative
tissue
oxidative
phosphorylation
NET PRODUCTS:
glucose
tumor
10%
GLYCOLYSIS
pyruvate
5% 85%
lactate
ENERGY, BUILDING BLOCKS,
NADPH
(B)
building
blocks
effect—so named because Otto Warburg first noticed the phenomenon in the early
twentieth century. It is this abnormally high glucose uptake that allows tumors to
MBoC6 n20.201/20.12
be selectively imaged in whole-body scans (see Figure 20–1), thereby providing a
way to monitor cancer progression and responses to treatment.
Figure 20–12 The Warburg effect in
tumor cells reflects a dramatic change in
glucose uptake and sugar metabolism.
(A) Cells that are not proliferating will
normally oxidize nearly all of the glucose
that they import from the blood to produce
ATP through the oxidative phosphorylation
that takes place in their mitochondria. Only
when deprived of oxygen will these cells
generate most of their ATP from glycolysis,
converting the pyruvate produced to lactate
in order to regenerate the NAD + that they
need to keep glycolysis going (see Figure
2–47). (B) Tumor cells, by contrast, will
generally produce abundant lactate even
in the presence of oxygen. This results
from a greatly increased rate of glycolysis
that is fed by a very large increase in the
rate of glucose import. In this way, tumor
cells resemble the rapidly proliferating
cells in embryos (and during tissue repair),
which likewise require for biosynthesis a
large supply of the small-molecule building
blocks that can be produced from imported
glucose (see also Figure 20–26).
Cancer Cells Have an Abnormal Ability to Survive Stress and DNA
Damage
In a large multicellular organism, there are powerful safety mechanisms that
guard against the trouble that can be caused by damaged and deranged cells. For
example, internal disorder gives rise to danger signals in the faulty cell, activating
protective devices that can eventually lead to apoptosis (see Chapter 18). To
survive, cancer cells require additional mutations to elude or break through these
defenses against cellular misbehavior.
Cancer cells are found to contain mutations that drive the cell into an abnormal
state, where metabolic processes may be unbalanced and essential cell components
may be produced in ill-matched proportions. States of this type, where the
cell’s homeostatic mechanisms are inadequate to cope with an imposed disturbance,
are loosely referred to as states of cell stress. As one example, chromosome
breakage and other forms of DNA damage are commonly observed during the
development of cancer, reflecting the genetic instability that cancer cells display.
Thus, to survive and divide without limit, a prospective cancer cell must accumulate
mutations that disable the normal safety mechanisms that would otherwise
induce a cell that is stressed, in this or in other ways, to commit suicide. In fact,
one of the most important properties of many types of cancer cells is that they fail
to undergo apoptosis when a normal cell would do so (Figure 20–13).
While cancer cells tend to avoid apoptosis, this does not mean that they rarely
die. On the contrary, in the interior of a large solid tumor, cell death often occurs
on a massive scale: living conditions are difficult, with severe competition among
the cancer cells for oxygen and nutrients. Many die, but typically much more by
necrosis than by apoptosis (Figure 20–14). The tumor grows because the cell birth
rate outpaces the cell death rate, but often by only a small margin. For this reason,
the time that a tumor takes to double in size can be far longer than the cell-cycle
time of the tumor cells.
Human Cancer Cells Escape a Built-in Limit to Cell Proliferation
Many normal human cells have a built-in limit to the number of times they can
divide when stimulated to proliferate in culture: they permanently stop dividing