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16
Cancer
16.1
16.2
16.3
16.4

Basic Properties of a Cancer Cell

The Causes of Cancer
The Genetics of Cancer
New Strategies for Combating Cancer

Experimental Pathways:

The Discovery of Oncogenes

ancer is a genetic disease because it can be traced to alterations within

specific genes, but in most cases, it is not an inherited disease. In an
inherited disease, the genetic defect is present in the chromosomes of a
parent and is transmitted to the zygote. In contrast, the genetic alterations that lead
to most cancers arise in the DNA of a somatic cell during the lifetime of the affected
individual. Because of these genetic changes, cancer cells proliferate uncontrollably,
producing malignant tumors that invade surrounding healthy tissue (Figure 16.1).
As long as the growth of the tumor remains localized, the disease can usually be
treated and cured by surgical removal of the tumor. But malignant tumors tend
to metastasize, that is, to spawn cells that break away from the parent mass, enter
the lymphatic or vascular circulation, and spread to distant sites in the body where
they establish lethal secondary tumors (metastases) that are no longer amenable to
surgical removal. The subject of metastasis is discussed in the Human Perspective
of Chapter 7 on page 248.
Because of its impact on human health and the hope that a cure might be developed, cancer has been the focus of a massive research effort for decades. Though
these studies have led to a remarkable breakthrough in our understanding of the
cellular and molecular basis of cancer, they have had very little impact on either preventing the occurrence of or increasing the chances of surviving most cancers. The
incidence of various types of cancer in the United States and the corresponding mortality rates are shown in Figure 16.2. Current treatments, such as chemotherapy and
radiation, lack the specificity needed to kill cancer cells without simultaneously damaging normal cells, as evidenced by the serious side effects that accompany these
treatments. As a result, patients cannot usually be subjected to high enough doses

Skull with Cigarette.

RESOURCE, NY.)

650

(BY VINCENT VAN GOGH, 1885, VAN GOGH MUSEUM, AMSTERDAM/ ART

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16.1 BASIC PROPERTIES OF A CANCER CELL

years, many different lines of cultured cells that were originally

derived from human tumors have been collected in cell banks
and are available for study. Alternatively, normal cells can
be converted to cancer cells by treatment with carcinogenic
chemicals, radiation, or tumor viruses. Cells that have been
transformed in vitro by chemicals or viruses can generally
cause tumors when introduced into a host animal. There are
many differences in properties from one type of cancer cell to
another. At the same time, there are a number of basic properties that are shared by cancer cells, regardless of their tissue
of origin.
At the cellular level, the most important characteristic of
a cancer cellwhether residing in the body or on a culture
dishis its loss of growth control. The capacity for growth
and division is not drastically different between a cancer cell
and most normal cells. When normal cells are grown in tissue
culture under conditions that promote cell proliferation, they
grow and divide at a rate similar to that of their malignant
counterparts. However, when the normal cells proliferate to
the point where they cover the bottom of the culture dish,
their growth rate decreases markedly, and they tend to remain
as a single layer (monolayer) of cells (Figure 16.3a,b). Growth
rates drop as normal cells respond to inhibitory influences
from their environment. Growth-inhibiting influences may
arise as the result of depletion of growth factors in the culture
medium or from contact with surrounding cells on the dish. In
contrast, when malignant cells are cultured under the same
conditions, they continue to grow, piling on top of one another to form clumps (Figure 16.3c,d ). It is evident that malignant cells are not responsive to the types of signals that
cause their normal counterparts to cease growth and division.
Not only do cancer cells ignore inhibitory growth signals,
they continue to grow in the absence of stimulatory growth
signals that are required by normal cells. Normal cells growing
in culture depend on growth factors, such as epidermal growth
factor and insulin, that are present in serum (the fluid fraction

FIGURE 16.1 The invasion of normal tissue by a growing tumor. This

light micrograph of a section of human liver shows a metastasized
melanosarcoma (in red) that is invading the normal liver tissue. (MICROASTRID AND HANNS-FRIEDER MICHLER/SCIENCE PHOTO
LIBRARY/PHOTO RESEARCHERS, INC.)
GRAPH BY

of chemicals or radiation to kill all of the tumor cells in their

body. Researchers have been working for many years to
develop more effective and less debilitating treatments.
Some of these newer strategies in cancer therapy will be
discussed at the end of the chapter.

16.1BASIC PROPERTIES
OF A CANCER CELL
The behavior of cancer cells is most easily studied when the
cells are growing in culture. Cancer cells can be obtained
by removing a malignant tumor, dissociating the tissue into
its separate cells, and culturing the cells in vitro. Over the

80

60

U.S. Cancer Deaths Per

100,000 Population

U.S. Cancer Cases Per

100,000 Population

70

50
40
30
20

Soft tissue

Brain

Ovarian

Pancreatic

Leukemia

Kidney

Melanoma

Bladder

Lymphoma

Colorectal

Lung

Breast

Prostate

10
0

651

FIGURE 16.2 The incidence of new cancer cases and deaths in the United States (20002003).

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Chapter 16 CANCER
Normal cells

Normal cells grow in monolayer

(b)

(a)
Cancer cells

FIGURE 16.3 Growth properties of normal and cancerous cells.

Normal cells typically grow in a culture dish until they cover the
surface as a monolayer (a and b). In contrast, cells that have been
transformed by viruses or carcinogenic chemicals (or malignant
cells that have been cultured from tumors) typically grow in
multilayered clumps, or foci (c and d ). (B AND D: COURTESY OF

Cancer cells grow in clumps (foci)

(c)

G. STEVEN MARTIN.)

(d)

Cell number

of blood), which is usually added to the growth medium (Figure 16.4). Cancer cells can proliferate in the absence of serum
because their cell cycle does not depend on the interaction between growth factors and their receptors, which are located at
the cell surface (page 623). As we will see below, this transformation is a result of basic changes in the intracellular pathways that govern cell proliferation and survival.
Normal cells growing in culture exhibit a limited capacity
for cell division; after a finite number of mitotic divisions, they
undergo an aging process that renders them unfit to continue to
grow and divide (page 495). Cancer cells, on the other hand, are
seemingly immortal because they continue to divide indefinitely. This difference in growth potential is often attributed to
the presence of telomerase in cancer cells and its absence in nor-

Cancer cells
+ serum growth factors

Cancer cells
serum growth factors

Normal cells
serum growth
factors
Normal cells
+ serum growth
factors

Time in culture
(days)

FIGURE 16.4 The effects of serum deprivation on the growth of normal and transformed cells. Whereas the growth of cancer cells continues regardless of the presence or absence of exogenous growth factors,
normal cells require these substances in their medium for growth to continue. The growth of normal cells levels off as the growth factors in the
medium are depleted.

mal cells. Recall from page 493 that telomerase is the enzyme
that maintains the telomeres at the ends of the chromosomes,
thus allowing cells to continue to divide. The absence of telomerase from most types of normal cells is thought to be one of the
bodys major defenses that protects against tumor growth.
The most striking alterations in the nucleus following
transformation occur within the chromosomes. Normal cells
maintain their diploid chromosomal complement as they
grow and divide, both in vivo and in vitro. In contrast, cancer
cells are genetically unstable and often have highly aberrant
chromosome complements, a condition termed aneuploidy
(Figure 16.5), which may occur primarily as a result of defects
in the mitotic checkpoint (page 584) or the presence of an abnormal number of centrosomes (see Figure 14.17c).1 It is evident from Figure 16.5 that the growth of cancer cells is much
less dependent on a standard diploid chromosome content
than the growth of normal cells. In fact, when the chromosome content of a normal cell becomes disturbed, a signaling
pathway is usually activated that leads to the self-destruction
(apoptosis) of the cell. In contrast, cancer cells typically fail to
elicit the apoptotic response even when their chromosome
content becomes highly deranged. Protection from apoptosis
is another important hallmark that distinguishes many cancer
cells from normal cells. Finally, it can be noted that cancer
cells often depend on glycolysis, which is an anaerobic metabolic pathway (Figure 3.24). This property may reflect the
high metabolic requirements of cancer cells and an inadequate
blood supply within the tumor. Under conditions of hypoxia
(reduced O2), cancer cells activate a transcription factor called
1

There is controversy as to whether the development of aneuploidy occurs at an

early stage in tumor formation and is a cause of the genetic instability that characterizes cancer cells, or is a late event and is simply a consequence of abnormal
cancer growth.

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653

FIGURE 16.5 Karyotype of a cell from a breast cancer line showing a

highly abnormal chromosome complement. A normal diploid cell
would have 22 pairs of autosomes and two sex chromosomes. The two
members of a pair would be identical, and each chromosome would be
a single continuous color (as in the karyotype of a normal cell in Figure 12.18b that uses a similar spectral visualization technique). The
chromosomes of this cell are highly deranged as evidenced by the

presence of extra and missing chromosomes and chromosomes of more

than one color. These multicolored chromosomes reflect the large numbers of translocations that have occurred in previous cell generations. A
cell with normal cell cycle checkpoints and apoptotic pathways could
never have attained a chromosome complement approaching that seen
here. (COURTESY OF J. DAVIDSON AND PAUL A. W. EDWARDS.)

HIF that induces the formation of new blood vessels and promotes the migratory properties of the cells, which may contribute to the spread of the tumor. However, even when
oxygen is plentiful, tumor cells continue to generate much of
their ATP by glycolysis. The end product of glycolysis is lactic
acid, which is secreted into the tumors microenvironment,
where it may promote tumor growth.
It is these properties, which can be demonstrated in culture, together with their tendency to spread to distant sites
within the body, that make cancer cells such a threat to the
well-being of the entire organism.

in chimney sweeps was due to their chronic exposure to soot.

Within the past several decades, the carcinogenic chemicals in
soot have been isolated, along with hundreds of other compounds shown to cause cancer in laboratory animals. In addition to a diverse array of chemicals, a number of other types of
agents are also carcinogenic, including ionizing radiation and
a variety of DNA- and RNA-containing viruses. All of these
agents have one property in common: they alter the genome.
Carcinogenic chemicals, such as those present in soot or cigarette smoke, can almost always be shown either to be directly
mutagenic or to be converted to mutagenic compounds by cellular enzymes. Similarly, ultraviolet radiation, which is the
leading cause of skin cancer, is also strongly mutagenic.
A number of viruses can infect mammalian cells growing
in cell culture, transforming them into cancer cells. These
viruses are broadly divided into two large groups: DNA tumor
viruses and RNA tumor viruses, depending on the type of
nucleic acid found within the mature virus particle. Among
the DNA viruses capable of transforming cells are polyoma
virus, simian virus 40 (SV40), adenovirus, and herpes-like
viruses. RNA tumor viruses, or retroviruses, are similar in
structure to HIV (see Figure 1.21b) and are the subject of the
Experimental Pathways, which can be found at the end of
the chapter. Tumor viruses can transform cells because they
carry genes whose products interfere with the cells normal
growth-regulating activities. Although tumor viruses were an
invaluable tool for researchers in identifying numerous genes

REVIEW

Describe some of the properties that distinguish cancer

cells from normal cells.
2. How do the properties of cancer cells manifest themselves
in culture?
1.

16.2 THE CAUSES OF CANCER

In 1775, Percivall Pott, a British surgeon, made the first
known correlation between an environmental agent and the
development of cancer. Pott concluded that the high incidence of cancer of the nasal cavity and the skin of the scrotum

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100

80

80

80

60

40

20

Incidence per 100,000

100

Incidence per 100,000

involved in cell transformation, they are associated with only a

small number of human cancers. Other types of viruses are,
however, linked to as many as 20 percent of cancers worldwide. In most cases, these viruses greatly increase a persons
risk of developing the cancer, rather than being the sole determinant responsible for the disease. This relationship between
viral infection and cancer is illustrated by human papilloma
virus (HPV), which can be transmitted through sexual activity
and is increasing in frequency in the population. Although the
virus is present in about 90 percent of cervical cancers, indicating its importance in development of the disease, the vast
majority of women who have been infected with the virus will
never develop this malignancy. HPV is also linked as a
causative agent to cancers of the mouth and tongue in both
men and women. An effective vaccine against this virus is now
available. Other viruses linked to human cancers include hepatitis B virus, which is associated with liver cancer; EpsteinBarr virus, which is associated with Burkitts lymphoma in
areas where malaria is common; and a herpes virus (HHV-8),
which is associated with Kaposis sarcoma.
Certain gastric lymphomas are associated with chronic
infection by the stomach-dwelling bacterium Helicobacter pylori, which is also responsible for ulcers. Recent evidence suggests that many of these cancers linked to infections are
actually caused by the chronic inflammation that is triggered
by the presence of the pathogen. Inflammatory bowel disease
(IBD), which is also characterized by chronic inflammation,
has been associated with an increased risk of colon cancer.
These findings have caused researchers to look more closely at
the general process of inflammation as a previously unexplored factor in the development of many types of cancers.
Determining the causes of different types of cancer is an
endeavor carried out by epidemiologists, researchers who study
disease patterns in populations. The causes of certain cancers
are obvious: smoking causes lung cancer, exposure to ultraviolet radiation causes skin cancer, and inhaling asbestos fibers
causes mesothelioma. But despite a large number of studies,
we are still uncertain as to the causes of most types of human
cancer. Humans live in complex environments and are exposed to many potential carcinogens in a changing pattern
over a period of decades. Attempting to determine the causes
of cancer from a mountain of statistical data obtained from
the answers to questionnaires about individual lifestyles has
proven very difficult. The importance of environmental factors (e.g., diet) is seen most clearly in studies of the children of
couples that have moved from Asia to the United States or
Europe. These individuals no longer exhibit a high rate of gastric cancer, as occurs in Asia, but instead are subject to an elevated risk of colon and breast cancer, which is characteristic of
Western countries (Figure 16.6).
There is a general consensus among epidemiologists that
some ingredients in the diet, such as animal fat and alcohol, can
increase the risk of developing cancer, whereas certain compounds found in fruits, vegetables, and tea can reduce that risk.
Several widely prescribed drugs appear also to have a preventive
effect. Long-term use of nonsteroidal anti-inflammatory drugs
(NSAIDs) such as aspirin and indomethacin has been shown to

Incidence per 100,000

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60

40

20

Stomach (male)

60

40

20

Breast (female)

Colon (male)

Japanese

Second-generation migrants

First-generation migrants

Caucasian Hawaiians

FIGURE 16.6 Changing cancer incidence in persons of Japanese descent following migration to Hawaii. The incidence of stomach cancer
declines, whereas that of breast and colon cancer rises. However, of the
three types of cancer, only colon cancer has reached rates equivalent to
Caucasian Hawaiians by the second generation. (FROM L. N. KOLONEL
ET AL, REPRINTED WITH PERMISSION FROM NATURE REVS. CANCER 4:3,
2004; COPYRIGHT 2004, MACMILLAN MAGAZINES LTD.)

markedly decrease the risk of colon cancer. They are thought to

have this effect by inhibiting cyclooxygenase-2, an enzyme
that catalyzes the synthesis of hormone-like prostaglandins,
which promote the growth of intestinal polyps. The cancersuppressing action of NSAIDs supports the idea that inflammation plays a major role in the development of various cancers.

16.3 THE GENETICS OF CANCER

Cancer is one of the two leading causes of death in Western
countries, afflicting approximately one in every three individuals. Viewed in this way, cancer is a very common disease. But
at the cellular level, the development of a cancer is a remarkably rare event. Whenever the cells of a cancerous tumor
are genetically scrutinized, they are invariably found to have
arisen from a single cell. Thus, unlike other diseases that require modification of a large number of cells, cancer results
from the uncontrolled proliferation of a single wayward cell
(cancer is said to be monoclonal ). Consider for a moment that
the human body contains trillions of cells, billions of which
undergo cell division on any given day. Though almost any
one of these dividing cells may have the potential to change
in genetic composition and grow into a malignant tumor,
this only occurs in about one-third of the human population
during an entire lifetime.
One of the primary reasons why a greater number of cells
do not give rise to cancerous tumors is that malignant transformation requires more than a single genetic alteration. We
can distinguish between two types of genetic alterations that
might make us more likely to develop a particular type of