transformation into a cancer cell. Even this
picture, although accurate in its essence, does
not represent a complete description of the
events involved in tumor formation. Additional
research revealed that as a tumor develops, the
cells of which it is composed become different
from one another as they acquire new traits
and form distinct subpopulations of cells within
the tumor. As shown in Figure 4, these changes
allow the cells that incorporate them to compete
with increasing success against cells that lack
23
Understanding Cancer
Cell Biology and Cancer
Cancerous cells also look and act differently from
approaches. The tumor microenvironment
normal cells. In most normal cells, the nucleus
influences the growth of the tumor and its ability
is only about one-fifth the size of the cell; in
to progress and metastasize. It can also limit the
cancerous cells, the nucleus may occupy most
access of therapeutics to the tumor, alter drug
of the cell’s volume. Tumor cells also often lack
metabolism, and contribute to the development
the differentiated traits of the normal cell from
of drug resistance. Because of their roles in all
which they arose. Whereas normal secretory
the stages of tumor development, elements of
cells produce and release mucus, cancers derived
the tumor microenvironment represent attractive
from these cells may have lost this characteristic.
therapeutic targets. Manipulating tumor-stromal
Likewise, epithelial cells usually contain large
interactions may be important in preventing or
amounts of keratin, but the cells that make
reversing malignant conversion and reestablishing
up skin cancer may no longer accumulate this
normal control mechanisms.
protein in their cytoplasms.
A unified view. By the mid-1970s, scientists
The key difference between normal and
started to develop the basis of our modern
cancerous cells, however, is that cancer cells have
molecular understanding of cancer. In particular,
lost the restraints on growth that characterize
the relationship Ames and others had established
normal cells. When grown in laboratory culture,
between mutagenicity and carcinogenicity
cancer cells demonstrate a variety of unusual
provided substantial support for the idea that
characteristics, including a lack of contact
chemical carcinogens act directly through their
inhibition (growth arrest when cells come
ability to damage cellular genes. This idea led to a
into contact with each other), a reduced
straightforward model for the initiation of cancer:
depen dence on the presence of growth factors
Carcinogens induce mutations in critical genes,
in the environment, and, often, the ability to
and these mutations direct the cell in which they
proliferate indefinitely.
occur, as well as all of its progeny cells, to grow
abnormally. The result of this abnormal growth
Significantly, a large number of cells in a tumor
appears—sometimes years later—as a tumor. The
are engaged in mitosis, whereas mitosis is a
model could even explain the observation that
relatively rare event in most normal tissues.
cancer sometimes appears to run in families. If
Cancer cells also do not interact normally with
cancer is caused by mutations in critical genes,
other cells in their environment. Tumor cells
then people who inherit such mutations would
can send signals to neighboring cells that may
be more susceptible to cancer’s development than
establish a more-favorable environment for
people who do not.
additional tumor growth and progression. These
signals may encourage the growth of new blood
As exciting as it was to see a unified view
vessels; stimulate the production of proteins that
of cancer begin to emerge from the earlier
disrupt cell adhesion, promote cell growth, or
confusion, cancer researchers knew their work
prevent programmed cell death (apoptosis);
was not finished. The primary flaw in their
and/or suppress the immune response.
emerging explanation was that the nature of
these cancer-causing mutations was unknown.
Therefore, a critical point that has emerged from
Indeed, the very existence of such mutations
research is the notion that a tumor is not simply a
had yet to be proven. Evidence from work with
ball of cancer cells but, rather, functions somewhat
cancer-causing viruses suggested that only a
like an organ—with vasculature, supporting tissue
small number of genes were involved in tumor
(or stroma), enzymes, proteins, growth factors, and
development, and evidence from cell biology
cytokines. Understanding the tumor necessitates
pointed to genes that normally control cell
understanding its tumor microenvironment.
division. But now scientists asked new questions:
The tumor microenvironment plays a critical role
Exactly which genes are involved? What are their
in tumor initiation and progression and may be
specific roles in the cell? How do their functions
an important factor in developing therapeutic
change as a result of mutation?
24
It would take another 20 years and a revolution
ensures that each tissue and organ in the body
in the techniques of biological research to answer
maintains a size and structure that meets the
these questions. However, today our picture
body’s needs. In fact, most proto-oncogenes
of the causes and development of cancer is so
and tumor-suppressor genes play key roles
detailed that scientists find themselves in the
in regulating cellular growth and survival
extraordinary position of not only knowing
during embryonic development. Mutations
many of the genes involved but also being able to
in these genes account for much of the
aim prevention, detection, and treatment efforts
uncontrolled cell division and evasion of
directly at these genes.
apoptosis that occurs in human cancers
(Table 8).
Cancer as a Multistep Process
A central feature of today’s molecular view of
The role of oncogenes. Most proto-oncogenes
cancer is that cancer does not develop all at once
code for proteins involved in molecular pathways
but rather does so over time, as a succession
that receive and process growth-stimulating
of genetic changes. Each change enables
signals from other cells in a tissue. Typically,
precancerous cells to acquire some of the traits
such signaling begins with the production of
that together allow the malignant growth of
a growth factor, a protein that stimu lates cell
cancer cells. It is clear that the normal cellular
division. Growth factors move through the
processes that control the cell cycle, cell survival,
spaces between cells and attach to specific
and the elimination of unnecessary or damaged
receptor proteins located on the surfaces of
cells are altered during tumorigenesis.
neigh boring cells. When a growth-stimulating
factor binds to such a receptor, the receptor
Two categories of genes play major roles in
conveys a stimulatory signal to proteins in the
trig gering cancer: proto-oncogenes and tumor-
cytoplasm. These proteins transmit stimulatory
suppressor genes. In their normal forms,
signals to other proteins in the cell until the
proto-oncogenes are involved in normal
division-promoting message reaches the cell’s
cellular processes that encourage cell division.
nucleus and activates a set of genes that help
Tumor-suppressor genes, on the other hand,
move the cell through its growth cycle. Most
play a role in inhibiting cell division, in
of the known oncogenes are proto-oncogenes
promoting apoptosis, or both. Together,
that have been altered or mutated in such a way
proto-onco genes and tumor-suppressor genes
that they promote cell growth in an abnormal or
coordinate the regulated growth that normally
uncontrolled fashion.
Table 8. Examples of proto-oncogenes and tumor-suppressor genes and some of the
human cancers associated with mutations in these genes.
Gene Type
Related Cancers
Proto-oncogene bcl-2
B-cell lymphoma
Proto-oncogene HER2/neu ( erbB-2)
Breast and ovarian cancers
Proto-oncogene c-Src
Colorectal cancers
Proto-oncogene c-Myc
Burkitt lymphoma
Tumor-suppressor gene BRCA1, BRCA2
Breast and ovarian cancers
Tumor-suppressor gene p53
Brain tumors; skin, lung, and head and neck cancers
Tumor-suppressor gene RB
Retinoblastoma; bone, bladder, and breast cancers
Tumor-suppressor gene APC
Colorectal cancers
25
Understanding Cancer
Cell Biology and Cancer
The protein products of oncogenes cause growth-
oncogene, the cell can experience the abnormal
promoting pathways to become overactive. As a
growth-promoting effects associated with that
result, the cell proliferates much faster than it
oncogene. However, if a cell contains only one
would if the mutation had not occurred. Some
inactive allele of a tumor-suppressor gene—and
oncogenes cause cells to overproduce growth
the other allele is still active—the active allele
fac tors. These factors can stimulate the growth
is usually sufficient to maintain normal growth-
of neigh boring cells, but they may also drive
inhibiting functions associated with that gene
excessive division of the cells that produced
and its protein product. Thus, in cases where a
them. Other oncogenes produce aberrant receptor
person is heterozygous for a particular tumor-
proteins that release stimulatory signals into
suppressor gene—that is, they inherit one
the cytoplasm even when no growth factors are
active and one inactive allele—then loss of
present in the environment. Still other oncogenes
heterozygosity, or the additional loss of the
disrupt parts of the signaling cascade that occurs
one functioning allele, is required for a complete
in a cell’s cyto plasm causing the cell’s nucleus to
loss of associated tumor-suppressor activity.
receive stimu latory messages continuously,
even when growth factor receptors are not
The body’s back-up systems. In addition to the
prompting them.
controls on proliferation, cells have at least three
other systems that can help them avoid runaway
The role of tumor-suppressor genes. To become
cell division. The first of these is the DNA-repair
cancerous, cells must also break free from the
system. This system operates in virtually every
inhibitory signals that normally counterbalance
cell in the body, detecting and correcting errors
these growth-stimulating pathways. In normal
in DNA. Across a lifetime, a person’s genes are
cells, inhibitory messages flow to a cell’s nucleus
under constant attack, both by carcinogens in
much like stimulatory messages do. But when
the environment and by chemicals produced
this flow is interrupted, the cell can ignore
in the cell itself. Errors also occur during DNA
these normally powerful inhibitory signals.
replication. In most cases, such errors are
rapidly corrected by the cell’s DNA-repair
Some tumor-suppressor genes code for
system. Should the system fail, however, the
proteins that inhibit progression of the cell
error (now a mutation) becomes a permanent
cycle. When such proteins are inactive or
feature in that cell and in all of its descendants.
absent, these inhibitory pathways no longer
function normally. Other tumor-sup pressor
The normally high efficiency of DNA repair is
genes appear to regulate the flow of signals
one reason why many years typically must pass
through growth-stimulating pathways; when
before all the mutations required for cancer to
these genes do not function properly, such
develop occur together in one cell. Mutations
growth-promoting pathways may operate
in DNA-repair genes themselves, however, can
with out normal restraint. Mutations in all
undermine this repair system in a particularly
tumor-sup pressor genes, however, apparently
devastating way. They damage a cell’s ability to
inactivate crit ical tumor-suppressor proteins,
repair errors in its DNA. As a result, mutations
depriving cells of this brake on cell division.
appear in the cell (including mutations in genes
that control cell growth) much more frequently
Most human cells contain two copies, or alleles,
than normal. For example, the BRCA1 and BRCA2
of each gene (with the exception of the sex
genes play a role in DNA repair, and mutations
chromosomes in males). When the alleles are
in them increase the risk of breast and ovarian
identical, a person is homozygous for the trait
cancers and possibly other cancers as well.
that the gene encodes. For proto-oncogenes,
it is important to note that when one allele
A second cellular back-up system prompts a cell
of a particular proto-oncogene is converted
to “commit suicide” by initiating apoptosis if some
(for example, through mutation) into an
essential component is damaged or its control
26
system is deregulated. This observation suggests
The multistep development of cancer. Cancer,
that tumors arise from cells that have managed to
then, does not develop all at once as a massive
evade such death. One way of avoiding apoptosis
shift in cellular functions resulting from a
involves the p53 protein, the product of a tumor-
mutation in one or two wayward genes. Instead,
suppressor gene. In its normal form, this protein
it develops step-by-step, over time, as a result of
not only halts cell division, but induces apoptosis
the accumulation of many molecular changes,
in abnormal cells; p53 is inactivated in many
each contributing some of the characteristics
types of cancers.
that eventually produce the malignant state. The
number of cell divisions that occur during this
The ability to avoid apoptosis contributes to
process can be astronomically large, and, as
cancer development. First, it contributes to the
you might expect, the time frame involved can
growth of tumors. Second, it makes cancer cells
be very long—it can take decades to accumulate
resistant to treatment. Scientists used to think
enough mutations to reach a malignant state.
that radiation and chemotherapeutic drugs killed
In addition, the rates of growth of tumors can
cancer cells directly by harming their DNA. It
vary, and it can take years for the tumors to be
is now known that even though these therapies
detectable.
do cause DNA damage, the resulting cell death
is due to the damaged cancer cells actively
Understanding cancer as a multistep process
killing themselves. This discovery suggests that
that occurs across long periods of time explains
cancer cells able to evade apoptosis will be less
a number of long-standing observations. A key
responsive to treatment than other cells.
observation is the increase in cancer incidence
with age. Most cases of cancer occur in people
A third back-up system limits the number of
who have lived long enough to have experienced
times a cell can divide, and so ensures that
a complex and extended succession of genetic
cells cannot reproduce endlessly. This system is
changes. In general, each event is rare. Therefore,
governed by a counting mechanism that involves
it can take a long time for cancer to develop.
the DNA segments at the ends of chromosomes.
Called telomeres, these segments shorten each
Understanding cancer in this way also explains
time a chromosome replicates. Once the telomeres
the increase in cancer incidence in people who
are shorter than a certain threshold length, they
experience unusual exposure to carcinogens or
trigger an internal signal that causes the cell to
who inherit predisposing mutations. Exposure
stop dividing. If the cells continue dividing, the
to carcinogens increases the likelihood that
telomeres can be lost completely and adjacent
certain harmful changes will occur, greatly
DNA damaged. Because DNA ends lacking
increasing the probability of developing cancer
telomeres are also recognized as inappropriate
during a normal life span. Similarly, inheriting
DNA breaks, the cell repair mechanisms can fuse
a cancer-susceptibility mutation means that
chromosomes together, a genetic crisis that is
instead of that mutation being a rare event,
inevitably fatal to the cell.
it has already occurred, and not just in one
or two cells, but in all of the body’s cells. In
Early observations of cancer cells grown in
other words, the process of tumor formation has
culture revealed that, unlike normal cells,
leapfrogged over one of its early steps. Now,
cancer cells can proliferate indefinitely. An
the accumulation of changes required to reach
enzyme called telomerase, which systematically
the malignant state, which usually requires
replaces the telomeric segments that are left
several decades to occur, can occur over a
off during each round of cell division, is absent
shorter period.
from most mature cells but present in most
cancer cells, where its action helps the cells
proliferate endlessly.
27
Understanding Cancer
Cell Biology and Cancer
Finally, understanding the development of
sex, age, and year of diagnosis. For example,
cancer as a multistep process also explains
Figure 5 shows SEER data for the age-adjusted
the lag time that often separates exposure to
cancer-incidence rates for the 10 most common
a cancer-causing agent and the development
sites for Caucasian and African American males
of cancer. This explains, for example, the
and females for 2000–2004.
observation that severe sunburns in children
can lead to the development of skin cancer
Cancer among children is relatively rare. SEER
decades later in adulthood. It also explains
data from 2005–2009 showed an incidence of
the 20-to-25-year lag between the onset of
only 15.4 cases per year per 100,000 children
widespread cigarette smoking among women
under age 15. Nevertheless, after accidents,
after World War II and the massive increase
cancer is the second leading cause of childhood
in lung cancer that occurred among women
death in the United States. Leukemias (5.0 per
in the 1970s.
100,000 per year) and cancer of the brain and
other nervous system organs (3.2 per 100,000
The Human Face of Cancer
per year) account for more than one-half of the
For most Americans, the real issues associated
cancers among children.
with cancer are personal. About 13.7 million
Americans alive today have a history of cancer,
Everyone is at some risk of developing cancer.
according to the National Cancer Institute. In
Cancer researchers use the term lifetime risk to
fact, cancer is the second leading cause of death in
indicate the probability that a person will develop
the United States, exceeded only by heart disease.
cancer over the course of a lifetime. In the United
States today, men have a 45 percent lifetime risk
Who develops cancer, and what are their chances
of developing invasive cancer, while women have
for surviving it? Scientists measure the impact
a 38 percent risk.
of cancer in a population by looking at three
elements: 1) the number of new cases per year
For a specific individual, however, the risk of
per 100,000 people (incidence rate), 2) the
developing a particular type of cancer may be
number of deaths per 100,000 people per year
quite different from someone else’s lifetime risk
(mortality, or death rate), and 3) the proportion
of developing the same type of cancer. Relative
of patients alive at some point after their initial
risk compares the risk of developing cancer
diagnosis of cancer (survival rate). Data on
between people in one group, such as those
incidence, mortality, and survival are collected
with a certain exposure or characteristic, and
from a variety of sources. For example, in the
people in another group, such as those who do
United States there are many statewide cancer
not have this exposure or characteristic. For
registries and some regional registries based on
example, according to the American Cancer
groups of counties, many of which surround large
Society, a person who smokes has a 10-to-20-fold
metropolitan areas. Some of these population-
higher risk of developing lung cancer than a
based registries keep track of cancer incidence
person who does not smoke.
in their geographic areas only; others also collect
follow-up information to calculate survival rates.
Scientists rely heavily on epidemiology to
help them identify factors associated with the
In 1973, the National Cancer Institute began
development of cancer. Epidemiologists look
the Surveillance, Epidemiology, and End Results
for factors that are common to c