C h a p t e r 7
Neoplasia
139
anti-apoptotic protein that protects tumor cells from
apoptosis.
Molecular and Cellular Pathways
Numerous molecular and cellular mechanisms with a
myriad of associated pathways and genes are known or
suspected to facilitate the development of cancer. These
mechanisms include defects in DNA repair mechanisms,
disorders in growth factor signaling pathways, evasion
of apoptosis, development of sustained angiogenesis,
and evasion of metastasis.
Mechanisms and genes that regulate repair of dam-
aged DNA have been implicated in the process of
oncogenesis (Fig. 7-7). The DNA repair genes affect
cell proliferation and survival indirectly through their
ability to repair nonlethal damage in other genes
including proto-oncogenes, tumor-suppressor genes,
and the genes that control apoptosis.
2.3
These genes
have been implicated as the principal targets of genetic
damage occurring during the development of a can-
cer cell. Such genetic damage may be caused by the
action of chemicals, radiation, or viruses, or it may
be inherited in the germ line. Significantly, it appears
that the acquisition of a single-gene mutation is not
sufficient to transform normal cells into cancer cells.
Instead, cancerous transformation appears to require
the activation of many independently mutated genes.
A relatively common pathway by which cancer cells
gain autonomous growth is by mutations in genes
that control signaling pathways between growth fac-
tor receptors on the cell membrane and their targets in
the cell nucleus.
2
Under normal conditions, cell prolif-
eration involves the binding of a growth factor to its
receptor on the cell membrane, activation of the growth
factor receptor on the inner surface of the cell mem-
brane, transfer of the signal across the cytosol to the
nucleus via signal-transducing proteins that function as
second messengers, induction and activation of regula-
tory factors that initiate DNA transcription, and entry
of the cell into the cell cycle (Fig. 7-8). Many of the pro-
teins involved in the signaling pathways that control the
action of growth factors in cancer cells exert their effects
through enzymes called
kinases
that phosphorylate pro-
teins. In some types of cancer such as chronic myeloid
leukemia, mutation in a proto-oncogene controlling
tyrosine kinase activity occurs, causing unregulated cell
growth and proliferation.
Carcinogenic
agent
• Activation of growth-promoting oncogenes
• Inactivation of tumor-suppressor genes
• Alterations in genes that control apoptosis
Unregulated cell
differentiation and growth
DNA repair
(DNA repair genes)
Failure of DNA
repair
Normal
cell
Malignant
neoplasm
DNA damage
FIGURE 7-7.
Flow chart depicting the stages in the
development of a malignant neoplasm resulting from exposure
to an oncogenic agent that produces DNA damage. When DNA
repair genes are present (red arrow), the DNA is repaired and
gene mutation does not occur.
P
P
P
P
P
Outer cell
membrane
Inner cell
membrane
P
MAP kinase
Active
Activation
Inactive
MAP kinase
Nucleus
Signal-
tranducing
proteins
Activation of
transcriptase
Growth factor
Growth factor receptor
FIGURE 7-8.
Pathway for genes regulating cell growth
and replication. Stimulation of a normal cell by a growth
factor results in activation of the growth factor receptor and
signaling proteins that transmit the growth-promoting signal
to the nucleus, where it modulates gene transcription and
progression through the cell cycle. Many of these signaling
proteins exert their effects through enzymes called kinases that
phosphorylate (P) proteins. MAP, mitogen-activating protein.
