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U N I T 1
Cell and Tissue Function
The accumulation of cancer cells may result not only
from the activation of growth-promoting oncogenes or
inactivation of tumor-suppressor genes, but also from
genes that regulate cell death through apoptosis or pro-
grammed cell death.
2,3,21,22
Faulty apoptotic mechanisms
have an important role in cancer. The failure of can-
cer cells to undergo apoptosis in a normal manner may
be due to a number of problems. There may be altered
cell survival signaling, down-regulation of death recep-
tors, stabilization of the mitochondria, or inactivation
of proapoptotic proteins. Alterations in apoptotic and
antiapoptotic pathways have been found in many can-
cers. One example is the high levels of the antiapoptotic
protein BCL2 that occur secondary to a chromosomal
translocation in certain B-cell lymphomas. The mito-
chondrial membrane is a key regulator of the balance
between cell death and survival. Proteins in the BCL2
family reside in the inner mitochondrial membrane and
are either proapoptotic or antiapoptotic. Since apoptosis
is considered a normal cellular response to DNA dam-
age, loss of normal apoptotic pathways may contribute
to cancer by enabling DNA-damaged cells to survive.
Even with all the genetic abnormalities described ear-
lier, tumors cannot enlarge unless angiogenesis occurs
and supplies them with the blood vessels necessary for
survival. Angiogenesis is required not only for continued
tumor growth, but also for metastasis.
2,3,23
The molecu-
lar basis for the angiogenic switch is unknown, but it
appears to involve increased production of angiogenic
factors or loss of angiogenic inhibitors. These factors
may be produced directly by the tumor cells themselves
or by inflammatory cells (e.g., macrophages) or other
stromal cells associated with the tumors. In normal cells,
the p53 gene can stimulate expression of antiangiogenic
molecules and repress expression of proangiogenic
molecules, such as vascular endothelial growth factor
(VEGF).
2
Thus, loss of p53 activity in cancer cells both
promotes angiogenesis and removes an antiangiogenic
switch. Because of the crucial role of angiogenic factors
in tumor growth, much interest is focused on the devel-
opment of antiangiogenesis therapy.
Finally, multiple genes and molecular and cellular
pathways are known to be involved in tumor invasion
and metastasis. Evidence suggests that genetic pro-
grams that are normally operative in stem cells dur-
ing embryonic development may become operative in
cancer stem cells, enabling them to detach, cross tis-
sue boundaries, escape death by anoikis or apoptosis,
and colonize new tissues.
24
The
MET
proto-oncogene,
which is expressed in both stem and cancer cells, is a
key regulator of invasive growth. Recent findings sug-
gest that adverse conditions such as tissue hypoxia,
which are commonly present in cancerous tumors,
trigger this invasive behavior by activating the MET
tyrosine kinase receptor.
Tumor Cell Transformation
The process by which carcinogenic agents cause nor-
mal cells to become cancer cells is hypothesized to be
a multistep mechanism that can be divided into three
stages: initiation, promotion, and progression (Fig. 7-9).
Initiation
involves the exposure of cells to doses of a
carcinogenic agent that induce malignant transforma-
tion.
2
The carcinogenic agents can be chemical, physical,
or biologic, and they produce irreversible changes in the
genome of a previously normal cell. Because the effects
of initiating agents are irreversible, multiple divided
doses may achieve the same effects as single exposures
of the same comparable dose or small amounts of highly
carcinogenic substances. The cells most susceptible to
mutagenic alterations in the genome are those that are
actively synthesizing DNA.
Promotion
involves the induction of unregulated
accelerated growth in already initiated cells by various
chemicals and growth factors.
2
Promotion is reversible
if the promoter substance is removed. Cells that have
been irreversibly initiated may be promoted even after
long latency periods. The latency period varies with the
type of agent, the dosage, and the characteristics of the
target cells. Many chemical carcinogens are called
com-
plete carcinogens
because they can initiate and promote
neoplastic transformation.
Progression
is the process whereby tumor cells acquire
malignant phenotypic changes. These changes may
promote the cell’s ability to proliferate autonomously,
invade, or metastasize. They may also destabilize its
karyotype.
Normal cell line
Normal cell
DNA damage
and cell mutation
Mutated cell
Progression
Promotion
Initiation
Carcinogenic agent
(chemicals,
radiation, viruses)
Activation of
oncogenes by
promoter agent
Malignant tumor
FIGURE 7-9.
The processes of initiation, promotion, and
progression in the clonal evolution of malignant tumors.
Initiation involves the exposure of cells to appropriate doses
of a carcinogenic agent; promotion, the unregulated and
accelerated growth of the mutated cells; and progression, the
acquisition of malignant characteristics by the tumor cells.
