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Chapter 11
Chemicals and Cancer
Chemicals and Cancer
• The etiology and pathophysiology of cancer is
extremely complex.
– Cancer is a collection of diseases that share
common aspects of cellular
pathophysiology.
– Cells may lose the normal regulatory control
mechanisms that keep growth and
replication in check with each other.
Chemicals and Cancer, cont.
• In the absence of regulatory controls, chaos
ensues.
• Although cancerous cells are clearly abnormal
by all measures of physiology, biochemistry,
and behavior, other patterns of growth are
recognized to be associated with changes in
normal cellular physiology.
Chemicals and Cancer, cont.
• Hyperplastic growth results in the production
of more cells than one would expect to see in
a particular tissue.
– Pregnancy induces hormone-dependent
hyperplasia in the breast.
– The end of gestation and cessation of lactation
return the tissue to its normal state.
Chemicals and Cancer, cont.
• Metaplasia refers to a change in growth that is not
necessarily concomitant with a change in mass.
– It can be induced environmentally.
– The columnar ciliated respiratory epithelia of the
airways, for example, can become nonciliated and
squamous from smoking.
– The epithelia may revert over time back to the
normal ciliated morphology given enough time
away from cigarettes and depending on the extent
of the exposure.
Chemicals and Cancer, cont.
• Unlike metaplasia and hyperplasia, neoplastic
growth generally persists or progresses.
Genomics
• Over the last decade a revolution in our
understanding of genetics has occurred, giving
rise to an area of study called genomics.
Genomics studies individual genes and
multiple gene interactions and the effect of
environmental stressors on them.
Genomics, cont.
• The importance of this has led to the formation of
the Centers for Disease Control and Prevention (CDC)
Office of Genomics.
• In 2004 the CDC and Institute of Medicine formed a
Committee on Genomics and the Public Health in the
21st Century, which included experts in the fields of
genetics, public health law, toxicology and
pharmacology, health care delivery, and others.
Genomics, cont.
• The following topics were included in the
discussions:
– Bridging genomics and public health
– Genomics as a science
– The clinical use of genomic information
– Gene-environment interactions
Neoplasms or Tumors
• The chemical mutations have additionally
been shown to be associated with many forms
of neoplasms or tumors.
• Some clarification of these and other
commonly used terms may be necessary (see
next two slides)
Neoplasms or Tumors
• Tumor: A mass of cells whose growth is atypical
when referenced to the normal surrounding tissue
structure.
• Neoplasm: Literally means “new growth” and is a
term commonly used the same way that the term
tumor is used.
• New formation: A mass whose growth is
incoordinate with the surrounding normal tissue and
that persists in the absence of an inciting stimulus.
Neoplasms or Tumors:
Definitions continued
• Benign tumor: A noncancerous tumor or growth that
remains confined to the growth site and may increase
in size but does not invade into distant tissues.
• Malignant tumor: Any cancerous tumor that may,
depending on the type of cancer, spread from its
primary growth site to potentially distant sites by its
ability to metastasize.
• Cancer: The general term to designate any tumor or
cells that have departed far from what is recognized as
normal in structure, growth, and/or replication.
Mutations in Genes That Regulate
Cell Growth and Differentiation
• Oncogenes
– Oncogenes are mutated forms of protooncogenes.
• Tumor Suppressor Genes
– These genes are sometimes referred to as
antioncogenes.
Oncogenes
• Oncogenes are mutated forms of protooncogenes.
• Proto-oncogenes are the normal regulatory
genes that code for cellular growth factors,
chemical messengers, and other cellular
mediators that orchestrate growth and
differentiation.
Oncogenes
• There are more than 100 different oncogenes
whose products include:
– Growth factors
– Receptors
– Cytoplasmic kinases
– Survival proteins
– Transcription factors
– Other proteins for signal transduction
Tumor Suppressor Genes
• Tumor suppressor genes play an important role in
maintaining a balance in the response of the cell to
positive and negative regulators of cellular growth.
• The gene codes for:
– Inducers of differentiation
– Cell adhesion molecules
– Inhibitors of cellular proliferation
– Transcription factors
– Inhibitors of angiogenesis
Tumor Suppressor Genes, cont.
• The importance of the tumor suppressor gene
is to limit the proliferation of mutated cells.
• Malfunction may be an increased risk factor
for cancer development and is supported by
observations in humans where there is a
family history of certain types of cancers, that
is, a mutated tumor suppressor gene has been
inherited.
Tumor Suppressor Genes, cont.
• Examples of mutated tumor suppressor genes
include:
– BRCA-1 associated with breast cancer
– APC associated with colon cancer
– p53 associated with over 50% of human
cancers
Tumor Suppressor Genes, cont.
• The p53 tumor suppressor gene is important
for the coding of enzymes that are important
in DNA repair, apoptosis, and regulation of cell
division:
– p53 senses DNA damage and induces cell
division arrest and DNA repair.
– Unrepairable DNA is directed to apoptosis
by the p53 gene.
P53: Guardian of the Genome
• Its homozygous loss leads to accumulation of
damaged DNA, which may lead to malignancy.
– A mutation of the p53 gene could result in a cell
escaping apoptosis.
– This becomes especially important for cells with
unrepaired DNA; they may continue to divide.
– If this happens, the pool of mutated DNA in a
tissue may be increased.
– Further mutations of these types of cells can
result in unregulated cell growth and division, the
hallmark of cancer.
P53: Guardian of the Genome
• Some studies suggest that the mutated p53
gene can be inherited, thus posing an
additional risk factor for the development of
cancer.
History of Chemical Carcinogenesis
• The area of chemical carcinogenesis today is
one of intense research that has led to a rich
scientific literature on the relationship
between chemical exposures and the
development and mechanisms that underlie
the process of carcinogenesis.
History of Chemical Carcinogenesis
• Early recognition of a relationship between
chemicals and an increased incidence of
cancer include the observations of:
– John Hill, who in 1761 observed a causal
relationship between nasal cancer in snuff users
– Sir Percival Pott, who in 1775 recognized that soot
and coal tar were the likely causal agents of
scrotal cancer.
History of Chemical Carcinogenesis
• Early recognition of a relationship between
cancer and genetics can be attributed to the
following researchers:
– Theodore Bovari
– Furthand Kahn
– James and Elizabeth Miller
Theodore Bovari
• In 1914 hypothesized that alterations in the
genetic material of the cells of the body are
somehow involved in the process that
produces cancer.
• This idea has been referred to as the somatic
mutation theory.
Furthand Kahn
• In 1934 experimentally used animal tumors to
test cells for their ability to produce tumors in
a tumor-free animal.
• It was observed that when the cells were
introduced into a tumor-free host animal,
similar tumors could be produced.
James and Elizabeth Miller
• In the 1950s recognized the relationship
between metabolism and the bioactivation of
carcinogens to produce metabolites that could
bind to the macromolecules of the cell.
• The process of metabolism was recognized to
produce electrophilic products, more reactive
than the unmetabolized parent chemicals,
thus establishing what has been referred to as
the electrophilic theory of carcinogenesis.
Characteristics of Cancer Cells
• The malignant phenotype refers to the
structural, functional, and behavioral
differences in the cells of malignant
neoplasms, including:
– Loss of contact growth inhibition
– Autonomy of proliferation
– Avoidance of apoptosis
– Aberrant differentiation
– Induction of angiogenesis
Tumor Angiogenesis, Metastasis,
and Staging
• A pathologist can assign the tumor a grade from 1 to
4 that corresponds to its degree of malignancy, with
4 being the most malignant and 1 being benign.
• The more malignant the tumor, the less organized
the cells of the tissue are and the more anaplastic or
dedifferentiated they appear.
• The prognosis worsens as cells become less
differentiated, that is, a well-differentiated cancer
carries a better prognosis than one that is poorly
differentiated.
Figure 11-2 Malignant neoplasms are
graded on the basis of differentiation.
Benign Tumors
• The tissues that make up the organs of our
body may consist of numerous cell types.
• Parenchymal cells are the functional cells that
are recognized as being unique to that organ.
– For example, in the liver we can recognize the
parenchyma as consisting of the hepatocyte,
which is the cell type that we associate with liver
function.
Benign Tumors
• Stromal cells, which are important to the
tissue, may be viewed as supportive in nature.
– The hepatocytes within the liver require
connective tissue and blood vessels to support
their function.
Benign Tumors, cont.
• Similarly, a neoplasm consists of both
parenchymal and stromal components.
• In benign neoplasms the parenchymal and
stromal cells may closely resemble those of
the normal surrounding tissue.
Table 11-1 Examples of Benign
Tumors and Their Tissues of Origin
Malignant Tumors
• Malignant tumors are similarly named for the tissue
from which the tumor is derived; one of three
suffixes is generally attached to create the name of
the cancer:
– Carcinomas: epithelia tissue origin and the most
common of all human malignancies
(approximately 90%). This cancer spreads
primarily through the lymphatic system.
– Sarcomas: connective tissue origin.
– Blastomas: derived from (or resembling)
embryonic tissue
Table 11-2 Examples of Malignant
Tumors and Their Tissues of Origin
Malignant Tumors
• The malignant tumor grows within its tissue of
origin; however, it may spread beyond these local
confines.
• Malignant tumor cells can invade into deeper
layers of tissue (invasion) and are capable of
metastasis as well.
• Malignant tissue has requirements for adequate
levels of oxygen, the removal of metabolic
wastes, and a supply of nutrients and other
factors.
Malignant Tumors, cont.
• Tumors release a number of factors that
collectively can be referred to as angiogenic
factors.
– Vascular endothelial growth factor is one such
factor that stimulates the growth of capillaries
into the tumor.
– This is the process of angiogenesis, which serves a
dual role in that it provides the vascular support
for the tumor proper and provides close access of
blood vessels for metastasis.
Malignant Tumors, cont.
• Another management approach in treating
patients with cancer is to use drugs such as
endostatin that inhibit the angiogenesis
process.
Metastasis
• Cancer cells can breach the basement membrane
and produce chemicals that can break down the
membrane, thus facilitating their entry into the
deeper tissue.
• Malignant cells that gain entry into the lymphatic
and blood vessels can travel within the circulation
until such time as they receive appropriate signals to
attach to the vessel wall and move into new tissue.
• This process is referred to as metastasis, and it
results in a secondary tumor.
Carcinogen Classification
• Based on Chemistry
– Thousands of suspected carcinogens have
already been tested for their ability to
produce mutations and cancer in laboratory
animals and in vitro systems.
– These chemicals fall into many different
categories of chemical agents based on
shared structural similarities.
Carcinogen Classification: Based on
Mechanism of Action
• Genotoxic
– Carcinogens can be classified by their mode of
action, genotoxic or nongenotoxic. Genotoxic
carcinogens are DNA reactive or DNA-reactive
metabolites capable of altering the integrity DNA
through direct interaction.
• Nongenotoxic
– Nongenotoxic carcinogens do not directly cause
DNA mutation. The mechanism of action is poorly
understood.
Carcinogen Classification
• Genomic information can be classified as
genetic or epigenetic. The genetic information
is the sequence of bases encoding the
proteins, and epigenetic information is the
regulation of gene expression by means other
than alterations in the DNA sequence.
• DNA methylation is also involved in DNA
repair, regulation of chromatin structure, and
genome instability.
Carcinogen Classification
• Epigenetic carcinogens can be defined as solid
state, hormonal, immunosuppressant,
cocarcinogenic, or promoter.
• The evidence for epigenetic mechanisms for
some chemicals includes the following
observations:
– Not all carcinogens are mutagens.
– Carcinogenesis is often associated with changes in
the methylation of DNA.
Case in Point
By the 1960s, evidence linked asbestos to the
development of certain types of cancer. Although it is
basically a chemically nonreactive substance to the
body, it does produce nonspecific irritant effects
believed to somehow encourage certain cells to
proliferate. Not all forms of asbestos are equally
capable of doing so. Fiber, shape, and size are crucial to
the carcinogenic properties of asbestos. Asbestosrelated cancers have been associated with long latency
periods, often decades.
Case in Point
Here is an example of how public health early warning
breaks down due to the relatively long latency period
between human exposures and an adverse health
outcome. Because asbestos stays in the lungs for a very
long period of time, additional exposure to other
carcinogens, such as those contained within cigarettes,
greatly increases the likelihood for cancer
development.
Exposure to Carcinogens
• The U.S. governmental regulatory definition of
a carcinogen is “any substance at any dose,
administered by any route, that increases
tumor incidence in rats.”
• The word tumor, as used in the regulatory
definition, is not synonymous with cancer
because we know that tumors can be either
benign or malignant.
Chemical-Induced Carcinogenesis
Is a Multistep Process
• Initiation - the genotoxic event that leads to
mutations of the DNA and places the affected cells at
a greater risk for tumor formation.
• Promotion - the second step in the carcinogenesis
process, which moves initiated cells further along
their transformation process. Exposure of initiated
cells to chemicals that stimulate cell proliferation,
such as irritating substances, results in the
production of a clone of proliferating cells within the
tissue.
Chemical-Induced Carcinogenesis
Is a Multistep Process
• Progression - Progression is the next step
toward the transformation of cells into a
tumor that is malignant. At this stage in the
process, and depending on the particular
tissue of origin of the cell, a high growth rate
and invasion into surrounding tissue may
occur.
Figure 11-5 Cancer is a multistep
process.
Mouse studies have shown
• Initiation must precede promotion for tumor
formation.
• Initiation followed by no promotion does not result in
tumor formation.
• Initiation followed by multiple exposures to promoter
(chronic exposure) results in tumor formation.
• Promoter by itself does not result in the production of
tumors.
• Promotion followed by initiation does not result in the
production of tumors.
Figure 11-8 Mouse skin initiationpromotion assay.
Informing the Public on
Carcinogens
• The federal government has the obligation to
inform the public about known and
anticipated human carcinogens.
• The Report on Carcinogens is a document
prepared in response to section 301 of the
U.S. Public Health Service Act.
Informing the Public on
Carcinogens
• It is stipulated that the Secretary of the Department
of Health and Human Services shall publish a report
that contains a list of all substances:
– That either are known to be human carcinogens or
may reasonably be anticipated to be human
carcinogens
– To which a significant number of persons residing
in the United States are exposed
• The responsibility for the preparation of this
document has been delegated to the NTP.
The Report on Carcinogens
• Prepared by the NTP
Executive Committee
• Agencies involved
include:
– Department of Health
and Human Services
– NIEHS/NTP
– Agency for Toxic
Substances and
Disease Registry
– FDA
– Consumer Product
Safety Commission
– EPA
– National Center for
Environmental
Health/CDC
– NIOSH
– Occupational Safety
and Health
Administration
– NIH/NCI