C h a p t e r 7
Neoplasia
141
Host and Environmental Factors
Because cancer is not a single disease, it is reasonable to
assume that it does not have a single cause. More likely,
cancers develop because of interactions among host and
environmental factors. Among the host factors that have
been linked to cancer are heredity, hormonal factors,
obesity, and immunologic mechanisms. Environmental
factors include chemical carcinogens, radiation, and
microorganisms.
Heredity
The genetic predisposition for development of cancer
has been documented for a number of cancerous and
precancerous lesions that follow mendelian inheritance
patterns. Two tumor suppressor genes, called
BRCA1
(breast carcinoma 1) and
BRCA2
(breast carcinoma 2),
have been implicated in a genetic susceptibility to breast
cancer.
2,3
These genes have also been associated with an
increased risk of ovarian, prostate, pancreatic, colon,
and other cancers.
Several cancers exhibit an autosomal dominant
inheritance pattern that greatly increases the risk of
developing a tumor. The inherited mutation is usually
a point mutation occurring in a single allele of a tumor-suppressor gene. Persons who inherit the mutant gene are
born with one normal and one mutant copy of the gene.
In order for cancer to develop, the normal allele must
be inactivated, usually through a somatic mutation. As
previously discussed, retinoblastoma is an example of a
cancer that follows an autosomal dominant inheritance
pattern. Approximately 40% of retinoblastomas are
inherited, and carriers of the mutant RB suppressor gene
have a 10,000-fold increased risk of developing retino-
blastoma, usually with bilateral involvement.
2
Familial
adenomatous polyposis of the colon also follows an
autosomal dominant inheritance pattern. In people who
inherit this gene, hundreds of adenomatous polyps may
develop, some of which inevitably become malignant.
Hormones
Hormones have received considerable research atten-
tion with respect to cancer of the breast, ovary, and
endometrium in women and of the prostate and testis
in men. Although the link between hormones and the
development of cancer is unclear, it has been suggested
that it may reside with the ability of hormones to drive
the cell division of a malignant phenotype.
2
Because of
the evidence that endogenous hormones affect the risk
of these cancers, concern exists regarding the effects on
cancer risk if the same or closely related hormones are
administered for therapeutic purposes.
Obesity
There has been recent interest in obesity as a risk factor
for certain types of cancer, including breast, endome-
trial, and prostate cancer.
25
The process relating obesity
to cancer development is multifactorial and involves a
network of metabolic and immunologic mechanisms.
Obesity has been associated with insulin resistance
and increased production of pancreatic insulin, both of
which can have a carcinogenic effect. Insulin enhances
insulin-like growth factor-1 (IGF-1) synthesis and its
bioavailability. Both insulin and IGF-1 are anabolic
molecules that can promote tumor development by
stimulating cell proliferation and inhibiting apoptosis.
Obesity has also been associated with increased levels
of sex hormones (androgens and estrogens), which act
to stimulate cell proliferation, inhibit apoptosis, and
therefore increase the chance of malignant cell transfor-
mation, particularly of endometrial and breast tissue,
and possibly of other organs (e.g., prostate and colon
cancer). And lastly, obesity has been related to a condi-
tion of chronic inflammation characterized by abnormal
production of inflammatory cytokines that can contrib-
ute to the development of malignancies.
Immunologic Mechanisms
There is substantial evidence for the participation of
the immune system in resistance against the progression
and spread of cancer.
2,3,26
The central concept, known
as the
immune surveillance hypothesis,
which was first
proposed by Paul Ehrlich in 1909, postulates that the
immune system plays a central role in protection against
the development of tumors.
27
In addition to cancer–host
interactions as a mechanism of cancer development,
immunologic mechanisms provide a means for the detec-
tion, classification, and prognostic evaluation of cancers
and a potential method of treatment.
Immunotherapy
(discussed later in this chapter) is a cancer treatment
modality designed to heighten the patient’s general
immune responses so as to increase tumor destruction.
The
immune surveillance hypothesis
suggests that
the development of cancer might be associated with
impairment or decline in the surveillance capacity of the
immune system. For example, increases in cancer inci-
dence have been observed in people with immunodefi-
ciency diseases and in those with organ transplants who
are receiving immunosuppressant drugs. The incidence
of cancer also is increased in the elderly, in whom there
is a known decrease in immune activity. The association
of Kaposi sarcoma with acquired immunodeficiency
syndrome (AIDS) further emphasizes the role of the
immune system in preventing malignant cell prolifera-
tion (discussed in Chapter 16).
It has been shown that most tumor cells have molec-
ular configurations that can be specifically recognized
by immune cells or antibodies. These configurations are
therefore called
tumor antigens
. Some tumor antigens are
found only on tumor cells, whereas others are found on
both tumor cells and normal cells; however, quantitative
and qualitative differences in the tumor antigens permit the
immune system to distinguish tumor from normal cells.
2
Virtually all of the components of the immune system
have the potential for eradicating cancer cells, including
T and B lymphocytes, natural killer (NK) cells, and mac-
rophages (see Chapter 15). The T-cell response, which
is responsible for direct killing of tumor cells and for
activation of other components of the immune system, is
