Section 2 The Etiology of Cancer

OBJECTIVES:
Upon completing this section, you should be able to:
1. Name the two most commonly accepted factors suspected of
causing cancer in humans.
2. Briefly describe the oncogene theory of cancer etiology.
3. Briefly discuss the viral etiology of some cancers.

23

Section 2 The Etiology of Cancer

Our current strategy against cancer is to eradicate
the disease after detection. The ideal strategy is
prevention, but this is not possible in most cases
because the exact cause or causes of most cancers
are unknown. The major exception to this is lung
cancer, in which there is no doubt that cigarette
smoking is the major contributing factor. Thus,
lung cancer is largely a preventable cancer.
More and more studies are revealing highly suggestive clues about the causes of cancer. In this
section, we will briefly survey the known and suspected causes of cancer, which fall into two broad
categories: environmental and hereditary. In addition, the oncogene concept, which is the most
recent theory of cancer etiology, will be reviewed.
Oncology nurses must be knowledgeable about the
risk factors that may predispose individuals and
family members to certain types of cancer. This
knowledge base will allow participation in screening programs and appropriate education and counseling. Table 5 lists a few known high-risk factors
for specific cancers.

ENVIRONMENTAL FACTORS
The role of environmental factors in human cancer
was demonstrated more than 200 years ago by the
English physician Percival Pott. In those days,
young boys hung on ropes to clean the soot from
inside chimneys. In 1775, Pott recognized a relationship between prolonged exposure to the irritating effects of chimney soot and the subsequent
development of scrotal cancer in these young boys.
Since then, evidence documenting environmental
factors in the etiology of cancer has continued to
accumulate. Today, it is estimated that environmental factors may be involved in a significant
percentage of cancers.
The Industrial Environment
Some occupations have been implicated in the
etiology of cancer. For example, workers in the
aniline dye industry have an increased risk of
developing bladder cancer. Lung cancer is more
prevalent among those who mine or work with
asbestos and those working with chromate or ura-

Table 5.
High-Risk Factors for Specific Cancers

24

Site

Predisposing Factor

Breast

Age over 40; late first full-term pregnancy; early-age menarche; late
menopause; familial history of breast cancer

Cervix

Women who begin sexual activity at an early age and have multiple
partners; human papilloma virus exposure

Colon and rectum

Familial polyposis; ulcerative colitis over many years; diet high in fat,
low in fiber

Lung

Cigarette smoking; exposure to asbestos, uranium, and nickel

Skin

Farmers and other outdoor workers; fair-skinned individuals who

sunburn easily

Mouth

Alcohol plus smoking; smokeless tobacco

Thyroid

X-ray therapy of neck as infants

Urinary bladder

Aniline-dye exposure; exposure to parasite Schistosoma haematobium;

cigarette smoking

Leukemia

Exposure to benzene; ionizing radiation

nium ores, especially if they also smoke cigarettes. Workers in nickel-refining plants are more
likely to develop cancer of the nasal sinuses than
are average individuals. Exposure to certain solvents, eg, benzene, has been associated with an
incidence of leukemia. Asbestos workers may
develop mesotheliomas of the pleural or peritoneal
cavities.

hydrates) in the typical Western diet, the incidence

of colon cancer has increased and stomach cancer
decreased. Populations who traditionally have a
non-Western diet high in fiber have a very low
incidence of colorectal cancer but a high incidence
of stomach cancer. The precise reasons for these
epidemiologic observations are uncertain, but
clearly diet influences cancer development.

Ultraviolet Light and Irradiation

Excessive exposure to sunlight is responsible for a
high incidence of skin cancer among farmers and
other outdoor workers. Fair-skinned individuals
who sunburn easily also are at high risk for developing skin cancer.

Research in Africa, England, and India by Dr.

Denis Burkitt and others has shown a direct relationship between the fiber content of food and
intestinal bulk. Bulk fiber represents nonabsorbable
sugars which increase intestinal mass and may
actually change the intestinal milieu, particularly
the transit time of carcinogens and the type of bacteria present. Unlike low-fiber foods, those with a
high fiber content produce greater waste bulk,
which moves through the intestine faster and produces large, soft stools that are easy to excrete.
Low-fiber foods may produce a reverse effect,
resulting in greater formation of potential carcinogens in the large bowel by the action of certain
bacteria on bile salts. Burkitt postulates that bile
salts in the colon may be increased by the greater
consumption of fat in Western countries. It is not
known whether bacteria may be affected by
changes in fat, fiber, or both food constituents. In
any event, a low-residue (low bulk fiber) diet produces a small stool that tends to take longer to pass
through the intestine, allowing the bacteria more
time to degrade bile salts. Thus, any carcinogen
formed has longer contact with the bowel lining
and a greater opportunity to cause cancer.

Cancer of the thyroid is more common in individuals who received irradiation to the neck as children.
The survivors of the A-bomb explosions at Hiroshima and Nagasaki are subject to an increased
incidence of cancers, particularly acute myelogenous leukemia.
Although not a common cause of cancer, radiation
exposure does increase the risk of lung cancer in
the uranium, strontium, nickel, and beryllium
industries. An increased incidence of leukemia has
been reported after exposure to radiation.
Cigarette Smoke
Cigarette smokers run a much greater risk of
developing lung cancer than do nonsmokers.
Increasing incidence of lung cancers in women is
directly linked to the increase in smoking of this
population. Smoking-related illnesses cause more
than 419,000 premature deaths every year. We
must emphasize that lung cancer is largely a preventable disease.
Diet
Aside from prostate cancer in men and breast cancer in women, the yearly number of new cases of
colorectal cancer (131,200) in the US is second
only to lung cancer. It is suspected that this high
incidence is due, in part, to diet. As refrigeration
and processed food have led to a reduction in
roughage and bulk (nondigestible complex carbo-

Diet also seems to be related to the high incidence

of liver cancer among certain groups of black
Africans living in Africa, compared to American
blacks. The high incidence among black Africans
in Africa correlates with the eating of foods (especially peanuts) contaminated with a fungus known
as Aspergillus flavus. This fungus produces a highly
carcinogenic substance known as aflatoxin. On
the other hand, chronic hepatitis is known to predispose to the development of liver cancer, and chronic
hepatitis is very common in Africa and Asia.

25

An association between high-fat diets and breast

cancer has been suggested from several different
sources of data. Epidemiologic data cannot, however, establish a firm cause-effect relationship, and
the resolution of this issue must await clinical studies of the influence of a reduced-fat diet on breast
cancer incidence.
Lung cancer has been associated with low intake
of vitamin A. Attempts to reduce the incidence of
lung cancer by administration of vitamin Alike
compounds (retinoids) have not been successful.
The American Cancer Society has recently developed dietary guidelines, as seen in Table 6.
Other Environmental Factors
The parasite Schistosoma haematobium, common
in some parts of the world such as Egypt, can
cause bladder cancer. The parasite enters the body
through the skin as workers stand in infested
waters. It then migrates to the bladder. Long-term
infestation is associated with an increased incidence of bladder cancer.

Smoking is also implicated in the risk of developing bladder cancer. The exact mechanism is
unknown, but statistics show that there is a correlation between smoking and an increased incidence
of bladder cancer.
Alcohol is thought to be a carcinogen or cocarcinogen (along with cigarette smoke) for cancers
of the head, neck, and esophagus. It may also play
a role in the etiology of liver cancer.
Women who become sexually active at an early
age and who have multiple partners are at greater
than normal risk of developing cervical cancer.

DRUGS AND CANCER

Immunosuppressive and Cytotoxic
Induced Cancer
A number of drugs in clinical use have also been
rarely associated with cancer. The majority of the
highly implicated agents are immunosuppressive
agents, principally the antimetabolites and gluco-

Table 6.
Nutrition and Cancer: Dietary Recommendations
Choose most of the foods you eat from plant sources.
Eat five or more servings of fruits and vegetables each day.
Eat other foods from plant sources, such as breads, cereals, grain products, rice, pasta,
or beans several times each day.
Limit your intake of high-fat foods, particularly from animal sources.
Choose foods low in fat.
Limit consumption of meats, especially high-fat meats.
Be physically active: achieve and maintain a healthy weight.
Be at least moderately active for 30 minutes or more on most days of the week.
Stay within your healthy weight range.
Limit consumption of alcoholic beverages, if you drink at all.
Adapted from Cancer Facts & Figures1997. Atlanta, GA: American Cancer Society; 1997:27. Reprinted by the permission of the American Cancer
Society, Inc.

26

corticosteroids. Table 7 lists the different drugs that

are associated with possible carcinogenesis in man.
It should be kept in mind that the risk of developing
drug-induced cancer is dependent on several nondrug factors: 1) age at first exposure (younger age
increases risk); 2) the long latency period between
exposure and cancer development (an average of
4050 years in industrial exposures, 510 years for
drugs); and 3) the presence of cocarcinogens (such
as cigarette smoking or ionizing radiation).
The most highly implicated carcinogenic drugs are
anticancer agents, and the major cancers produced

are leukemias and lymphomas. Acute myelocytic

leukemia is an unfortunate and rare complication
of alkylating agents such as melphalan and
cyclophosphamide.
The drugs most commonly associated with second
neoplasms are the alkylating agents. These drugs
bind to DNA and induce mutations. Radiotherapy
potentiates the leukemogenic action of alkylating
agents. Immunosuppression secondary to chemotherapy, AIDS, or immunosuppressive drugs may
lead to Epstein-Barr virus (EBV)induced nonHodgkins lymphoma.

Table 7.
Cancers Associated With Drugs in Common Clinical Usage
Agent

Patient
Population

Cyclophosphamide

Cancer

Bladder cancer,
acute myelogenous
leukemia (AML)

Melphalan

Multiple myeloma

AML

Azathioprine and
cyclosporine

Allotransplant
recipients

Non-Hodgkins
lymphomas,
skin cancers

Nitrogen mustard,
procarbazine,
ionizing radiation

Cancer

AML

Synthetic
(diethylstilbestrol)

Females

Vagina, cervix
(adenocarcinoma)

Phenacetin-containing
drugs

Over-the-counter
pain treatment

Renal pelvis
carcinoma

Associated Cancers

27

HORMONES AND CANCER

Some hormones are thought to possess carcinogenic potential and this is important in three cancers.
1. Breast Cancer: Large doses of estrogens, when
given continuously, can cause breast cancer in
susceptible strains of mice. Animal studies also
show that estrogen is a cocarcinogen; eg, it is
carcinogenic when administered experimentally
along with another cancer-causing agent such
as x-rays or the chemical methylcholanthrene.
The animal data have raised concern that women
who take birth control pills, or who receive
estrogen supplements at menopause, might incur
an increased risk of cancer. Most of the largescale studies suggest that exogenous estrogen
probably is not a significant factor in human
breast cancer, although some experts still feel
that the safety of estrogen has not been proven.
2. Endometrial Cancer: Many scientists now suspect that estrogen increases the hazard of developing cancer of the uterine endometrium. This is
based upon several case-control studies reporting an increased risk of malignancy in women
receiving estrogen supplementsthough other
studies report no such increases, and still other
studies find an actual decrease in the risk.
Despite the possible hazard of increased malignancy, many doctors now feel that low-dose
estrogen supplementation is safe for menopausal
or oophorectomized women who have symptoms of estrogen deficiency. One consequence
of low estrogen levels is osteoporosis, which
greatly increases the risk of serious injury from
bone fractures.
3. Vaginal Adenocarcinoma: In 1947, it was
thought that synthetic estrogens such as DES
(diethylstilbestrol) were well tolerated in pregnancy, safe for the fetus, and effective for preventing abortion. As a result, DES and related
synthetic estrogens were widely prescribed

28

until a 1977 study showed that the daughters of

DES-treated mothers had an increased incidence of vaginal dysplasia and carcinoma.
Because the use of DES in pregnancy has been
stopped, this complication will cease to be a
problem in a few years.
4. Prostate Cancer: The most important risk factor in prostate cancer is age, but testosterone
after being metabolized to dihydrotestosterone
is a potent stimulator of cell division in prostate
cells. Dihydrotestosterone may be involved in
malignant transformation, and studies are under
way to determine whether inhibition of dihydrotestosterone production will reduce the incidence of prostate cancer.

HEREDITARY FACTORS
Evidence supporting the role of genetic factors in
cancer comes primarily from animal studies.
Breeding experiments with mice led to the development of mouse families with very high incidences of specific cancers, such as lung and breast
cancer. Other selected matings of mice produced
families that were essentially cancer-free.
Statistical evidence supports the genetic etiology
of cancer in humans. The best example of a
hereditary cancer in man is retinoblastoma, a relatively uncommon neoplasm of children. However, genetic factors probably play an important
role in the familial tendencies toward some common cancers such as cancer of the colon (familial
polyposis), hereditary nonpolyposis colorectal cancer (HNPCC), breast cancer, and stomach cancer.
A genetic history is an essential part of every cancer patients medical history. Breast cancer is one
of the best examples of a malignancy for which a
genetic predisposition influences clinical practice.
The incidence of breast cancer may double or more
than double when one or more female relatives of a
woman have had breast cancer. Hence, knowledge
of a familys cancer history can help in planning
early detection programs for high-risk subjects.

The recent identification of two genes associated

with an increased risk of breast cancer, ovarian
cancer, and prostate cancer (BRCA1, BRCA2) has
raised the possibility of testing for genetic susceptibility. As yet, the technological advances necessary to move this from a research to a practical
clinical setting have not been made.

ONCOGENES
The most enduring hypothesis concerning the origin of cancer is that some genetic alteration,
induced by elements in the environment, acts on a
genetically determined predisposition and results
in the unregulated proliferation of cells.
One very exciting new area of cancer research,
which serves to combine hereditary and environmental factors, is the study of oncogenes.
Oncogene is derived from two Greek words: Onkos
means bulk or mass and refers to a tumor, or has
some relationship to a tumor, while gene, which is
the functional unit of heredity, is derived from the
word genos, meaning birth. Therefore, something
that causes a tumor is said to be oncogenic and a
gene that when activated causes a cancer is an
oncogene.
Each cell contains a set of genes that are essential
for embryonic tissue development, tissue repair,
and normal proliferation. The control of stem cell
proliferation is exercised via these special genes.
It now appears that these genes are activated by
radiation, chemicals, viruses, and other as yet
undefined factors. These oncogenes then act
as cellular transforming genes, causing uncontrolled proliferation of previously normal cells.
Certain proteins produced by oncogenes have
been identified, and in some cases the proteins
form cell surface receptors for growth factors,
intracellular signals that turn on or turn off cell
growth, and factors that alter the expression of
DNA. Our understanding of the biochemical
mechanisms involved in cancer offers the potential for improved detection, prognosis, and treatment. Table 8 lists some of the oncogenes that
have been associated with specific human cancers.

Many of these oncogenes are silent until the gene

moves or translocates from one chromosome to
another. This chromosomal breakage and reunion
is known to occur in several cancers, including
chronic leukemias and lymphomas.
Some genes suppress abnormal cell growth and
when they are damaged or missing, cancer is more
likely to develop. The best example of this type of
gene is the retinoblastoma (RB) gene.

VIRUSES
Oncogenes were first identified in viruses that
cause cancer in animals. Later it was learned that
the viruses had captured a normal host gene that
regulated stem cell proliferation. These oncogenic
viruses caused cancer by activating that normal
host gene inside a host cell.
lt is known that members of a group of small DNA
viruses called papovaviruses cause a variety of animal tumors. Among them are the papilloma
viruses, responsible for papillomas in rabbits, and
the polyoma virus, which causes malignant tumors
of the parotid gland, mammary gland, and kidney
as well as subcutaneous fibrosarcomas when
injected into mice. Also, ribonucleic acid (RNA)
viruses have been shown to cause leukemias in
chickens, mice, and cats, and mammary carcinomas in mice.
A human retrovirus, human T-cell lymphotropic
virus (HTLV-1), has been recognized as the etiologic agent of an aggressive form of leukemia
known as adult T-cell leukemia/lymphoma (ATLL).
Also, in African Burkitts lymphoma, a viral etiology seems possible. Generally, it occurs between
the ages of 2 and 14, with a peak incidence at age
7. It is a cancer of the B-cell lymphocytes, and it
is common in areas of the world where malaria is
endemic.
Viral involvement in Burkitts lymphoma is difficult to discount because cells from nearly every
biopsy of African Burkitts lymphoma contain a
herpes virus: the Epstein-Barr virus. EBV is also
associated with carcinoma of the nasopharynx, a
29

common malignancy in Southern China, Malaysia,

Indonesia, and parts of Africa. EBV has also been
implicated in the etiology at Hodgkins disease and
in non-Hodgkins lymphoma in patients who are
immunosuppressed. Another factor implicating

viruses in causing human cancers is that carcinomas of the cervix are more common after infection
by the type II herpes virus. In spite of such data,
however, more research is needed to prove conclusively that viruses cause human cancers. Further-

Table 8.
Examples of Oncogenes and Cancer Suppressor Genes
Associated With Human Cancers

30

Gene

Tumor

MYC

Many solid tumors and hematologic malignancies

N-MYC

Neuroblastoma and lung cancers

L-MYC

Small cell lung cancer

RAS

Many solid tumors

p53

Many sporadic malignancies (most commonly mutated cancer gene);

when inherited, causes the Li-Fraumeni familial cancer syndrome

BRCA1

Breast cancer, ovarian cancer, prostate cancer

BRCA2

Breast and ovarian cancer

APC

Colon familial polyposis (a premalignant condition)

MSH, MLH

Mismatch repair genes associated with hereditary nonpolyposis

colon cancer (HNPCC)

DCC

Colon cancer

RB

Retinoblastoma and some other tumors

NF1, NF2

Neurofibroma

C-ERB-2

Breast cancer (also called HER-2/neu), other tumors

ABL

Chronic myeloid leukemia

WT1

Wilms tumor

ATM

Ataxia telangiectasia associated with multiple cancers

MEN

Multiple endocrine neoplasia syndrome

HPC1

Prostate cancer

VHL

Renal and some other cancers

PTCH

Basal cell cancers (Gorlin syndrome)

p16

Melanoma

BCL-2

Non-Hodgkins lymphoma

more, we need to determine whether these viruses

cause human cancer directly or indirectly by activating a host oncogene. Table 9 lists the human
cancers that have been associated with a specific
oncogenic virus.

SUMMARY
This section has dealt with the causes of cancer.
Environmental factors may be important in a significant percentage of human cancers. Such factors as exposure to radiation, nickel dust, uranium
dust, strontium, and cigarette smoking are all suspected causes of cancer. Dietary factors, immunosuppressive and cytotoxic drugs, and hormones
also play a role.
It is believed that heredity plays a role in developing cancer. Statistical evidence supports a genetic
etiology of some cancers in humans.

Some scientists think that cancer is not caused by a

single agent or factor, but by the interplay of several factors that combine to cause the normal
cell to change into a malignant cell. lt is generally believed that transformation of the normal cell
into a malignant cell occurs when one or more
oncogenes are activated.
Selected Bibliography
Cartmel B, Reid M: Cancer control and epidemiology. In: Groenwald SL,
Frogge MH, Goodman M, Yarbro CH, eds: Cancer Nursing Principles and
Practice. 4th ed. Boston, MA: Jones and Bartlett; 1997:5074.
Cooper GM: Oncogenes. 2nd ed. Boston, MA: Jones and Bartlett; 1995:7273.
DeVita VT Jr, Hellman S, Rosenberg SA, eds: Cancer: Principles & Practice of
Oncology. 5th ed. Philadelphia, PA: JB Lippincott; 1997.
Weisburger JH, Williams GM: Causes of cancer. In: Murphy GP, Lawrence W,
Lenhard RE, eds: American Cancer Society Textbook of Clinical Oncology. 2nd
ed. Atlanta, GA: American Cancer Society; 1995:1039.
Yarbro JW: Milestones in our understanding of the causes of cancer. In:
Groenwald SL, Frogge MH, Goodman M, Yarbro CH, eds: Cancer Nursing
Principles and Practice. 4th ed. Boston, MA: Jones and Bartlett; 1997:316.

Table 9.
Human Viruses Associated With Cancer*
Virus

Type

Associated Cancer

Cofactors

Herpes

Epstein-Barr

Burkitts lymphoma
Lymphoma

Malaria
Immunodeficiency

Papillomavirus

HPV-16, -18, -33, -39

Anogenital cancers

HPV-5, -18, -17

Skin cancer

Smoking (?),
other factors
Sunlight, genetic
disorders, immune
suppression

Hepatitis

HBV, HCV

Hepatocellular
carcinoma

Aflatoxin,
alcohol

Retrovirus

HTLV-1

Adult T-cell
leukemia/lymphoma

Uncertain

HTLV-2

Hairy cell leukemia

Unknown

* Modified from Howley PM, Ganem D, Kieff E: Etiology of cancer: DNA viruses. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of
Oncology. 5th ed. Philadelphia, PA: Lippincott-Raven; 1997:169.

31

Section 2
EVALUATION FRAMES
1. Name and describe the two most common factors suspected of causing cancer.
a)

b)

2. Briefly explain the oncogene theory.

32

ANSWERS
1. a) Environmental factors may contribute to a
significant percentage of human cancers.
Such factors as radiation exposure; working
around nickel, uranium, and strontium;
cigarette smoking; hormones; and lack of
roughage and bulk in the diet are all suspected potential environmental contributing causes of cancer. Viruses may also be
involved in cancer causation.

2. Oncogenes are normal host genes conserved in

evolution probably because they are necessary
for growth and repair. When these genes are
activated by an environmental or hereditary factor, they may produce cancer.
If you completely understood the preceding material, proceed to Section 3. Otherwise, continue with
the reinforcement frames on the next page.

b) Heredity plays a role in causing cancer.

Statistical evidence supports a genetic contribution to cancer in humans.

33

Section 2
REINFORCEMENT FRAMES
2.1 In Section 2 we discussed the causes of cancer. The two commonly accepted carcinogenic factors are environment and ...................
heredity
2.2 Anything that causes cancer or is suitable for
the formation and development of neoplasms
is called an oncogenic agent. Thus, those
viruses thought to be carcinogenic are known
as ............................. viruses.
oncogenic
2.3 Oncogenic viruses are viruses thought to
cause certain types of ..................
cancer
2.4 Hormones have been implicated, often
wrongly, as causes of cancer. Scientific
research has shown that estrogen probably
does not cause ............................ cancer, but
that it may increase the risk of developing
.................... cancer. A synthetic hormone
that has been linked to vaginal cancer is .........
.
breast endometrial DES

34

2.5 Radiation exposure; working around nickel,

uranium, and strontium; cigarette smoking;
and lack of roughage and bulk in the diet are
all .................................. suspected of causing
cancer.
environmental factors
2.6 There is evidence of a genetic or hereditary
tendency for developing cancer. In other
words, in some types of cancer it is suspected
that .............................. plays a role in causing
cancer.
heredity
2.7 State two factors involved in carcinogenesis.
a)
b)
environmental factors
heredity