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

1114 Chapter 20: Cancer
having mutations in the Rb pathway, 45% in the Ras/PI3K pathway (defined more
narrowly than in the glioblastoma study), and more than 96% in the p53 pathway.
Allowing for additional pathway components not included in the analysis,
it seems that most cases of this type of cancer, too, have mutations disrupting the
same three controls, leading to misregulated cell growth, misregulated cell proliferation,
and abnormal disregard of stress and DNA damage. It seems that these
three fundamental controls are subverted in one way or another in virtually every
type of cancer.
We have devoted an entire chapter to the cell cycle and growth controls (Chapter
17). Some important details of the other two control pathways are reviewed
next.
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells to
Grow
Cell proliferation is not simply a matter of progression through the cell cycle; it
also requires cell growth, which involves complex anabolic processes through
which the cell synthesizes all the necessary macromolecules from small-molecule
precursors. If a cell divides inappropriately without growing first, it will get
smaller at each division and will ultimately die or become too small to divide.
Cells appear to require two separate signals to grow and divide (Figure 20–26).
Cancer depends, therefore, not only on a loss of restraints on cell-cycle progression,
but also on disrupted control of cell growth.
The phosphoinositide 3-kinase (PI 3-kinase)/Akt/mTOR intracellular signaling
pathway is critical for cell growth control. As described in Chapter 15, various
extracellular signal proteins, including insulin and insulin-like growth factors,
mitogen
growth factor
glucose
growth factor required for
nutrient uptake and utilization
glucose transporter
activation
needed to
drive the
cell cycle
activation
needed for
nutrient uptake
and utilization
increased
glucose
transport
CYTOSOL
P
P
activated receptor
tyrosine kinase
activation of
PI 3-kinase
increased
glycolysis
active
mTOR
mTOR
P
P
activated Akt
CELL GROWTH AND PROLIFERATION
increased
pyruvate
INCREASED
PROTEIN
SYNTHESIS
active ATP citrate
lyase (ACL)
P
(A)
(B)
TCA
cycle
mitochondrion
citrate
excess citrate
exported to
cytosol
acetyl CoA
LIPID SYNTHESIS
MEMBRANE BIOSYNTHESIS
REQUIRED FOR CELL GROWTH
Figure 20–26 Cells seem to require two types of signals to proliferate. (A) In order to multiply successfully, most normal cells are suspected to
require both extracellular signals that drive cell-cycle progression (shown here as blue mitogen) and extracellular signals that drive cell growth (shown
here as red growth factor). How mitogens activate the Rb pathway to drive entry into the cell cycle is described in Figure 17–61. (B) Diagram of
the signaling system containing Akt that drives cell growth through greatly stimulating glucose uptake and utilization, including a conversion of the
excess citric acid produced from sugar intermediates in mitochondria into the acetyl CoA that is needed in the cytosol for lipid synthesis and new
membrane production. As indicated, protein synthesis is also increased. This system becomes abnormally activated early in tumor progression. TCA
cycle indicates the tricarboxylic acid cycle (citric acid cycle).