Transcript Richards_CH11x

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.
– 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:
– 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 over time 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 with respect to structure, growth, and
replication.
Mutations & Cancer Development
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 proto-oncogenes.
• Proto-oncogenes are the normal regulatory genes
that code for cellular growth factors, chemical
messengers, and other cellular mediators that
orchestrate growth and differentiation.
• 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
• 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
• p53 is a 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 because they may continue to divide.
– If they continue to divide in an unregulated manner, 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.
• 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.
• 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
History of Chemical Carcinogenesis
• Researcher:
– 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.
History of Chemical Carcinogenesis
• Researcher:
– 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.
History of Chemical Carcinogenesis
• Researchers:
– 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.
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.
– 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.
Naming of Benign Neoplasms
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
Naming of Malignant Tumors
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.
• 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.
• 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.
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.
• 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.
Cancer is a Multistep Process
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.
• 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.