Transcript Abnormal Cell Growth

Abnormal Cell Growth
I. OVERVIEW
• Cells are often lost through:
– Death (apoptosis and necrosis),
– Sloughing (e.g., shedding of cells lining the
gastrointestinal tract and skin), or
– Injury (e.g., bleeding).
• New cells replace cells at the same rate they are
lost, a highly regulated state of balance known
as homeostasis.
• If normal cellular regulatory mechanisms
malfunction, unregulated and unchecked cell
division may result, i.e., cancer.
• Protooncogenes regulate or produce proteins that
regulate normal cell growth and development.
• Mutations in protooncogenes may convert them
from regulatory genes into cancer-causing
oncogenes.
• In addition, mutations that create a loss of
function in genes known as tumor suppressor
genes may also induce cancer.
• Most genetic changes that occur during
carcinogenesis (transformation of normal cells to
cancer cells) are somatic mutations. Each time a
cell divides, there is a chance of somatic mutation;
therefore, there is always a low background risk
for cancer. A far more prevalent cause of cancer is
environmental exposure.
I. GENES AND CANCER
A. Protooncogenes and oncogenes
- Protooncogenes are genes whose protein
products control cell growth and
differentiation.
- These genes undergo mutations causing
qualitative and quantitative changes in
gene products and are then called
oncogenes.
1. Protooncogenes
• Protooncogenes stimulate the cell cycle and have
been identified at all levels of the various signal
transduction cascades that control cell growth,
proliferation, and differentiation.
• As normal regulatory elements, proto-oncogenes
function in a wide variety of cellular pathways
(Figure-1).
• Mutations can occur in any of the steps involved in
regulating cell growth and differentiation. When
such mutations accumulate within a particular cell
type, the progressive deregulation of growth
eventually produces a cell whose progeny forms a
tumor.
Figure 1. Protooncogenes and their
roles in regulating growth.
2. Several ways of activating
protooncogenes to oncogenes:
• Point mutations, insertion mutations, gene
amplification, chromosomal translocation,
and/or changes in expression of the
oncoprotein can all result in deregulated
activity of these genes (Figure 2).
Figure 2. Mechanism of conversion of protooncogenes to oncogenes.
Tumor Suppressor Genes
Tumor suppressor genes are important for
maintaining normal cell growth control by
curtailing unregulated progression through the cell
cycle. Situations that diminish tumor suppressor
gene function may lead to neoplastic changes.
1. Loss of function: Loss of tumor suppressor
genes predisposes cells to cancer.
- Protein products of tumor suppressor genes
repress cell growth and division.
- Loss of gene function can lead to cell
transformation
2. p53-guardian of the genome:
- Most frequently inactivated tumor suppressor gene and
most often implicated in cancer development
- More than half of human cancers show p53 mutations
- Loss of p53 function can contribute to genomic
instability within cells
p53 Functions
- Regulates gene expression and controls several key genes
involved in growth regulation
- Facilitates DNA repair. p53 senses the damage and
causes G1 arrest of the cells until damage is repaired
- Activates apoptosis of damaged cells when DNA is
beyond repair
- p53 suppresses telomerase activity
p53 -- guarding the genome
Dominant and recessive nature of
oncogenes and tumor suppressor genes
• When proto-oncogenes undergo mutations they are
“activated” to oncogenes. Because these genes normally
regulate growth, mutations in them often favor the
unregulated growth of cancer.
• Generally, tumor suppressor genes are “inactivated” by
mutations and deletions, resulting in the loss of
function of the protein and in unregulated cell growth.
• Both copies of the tumor suppressor genes have to be
mutated or lost for loss of growth control; therefore,
these genes act recessively at cell level. Oncogenes, on
the other hand, are dominant in action requiring
mutation of only one copy of a protooncogene
Oncogenes are dominant in action at the
cell level and tumor suppressor genes are
recessive.
MicroRNAs as oncogenes and tumor suppressors
• MicroRNAs (miRNAs) regulate gene expression by
controlling the levels of target RNA
posttranscriptionally.
• They are encoded within the noncoding and intron
regions of different genes and are transcribed into RNA,
but not protein.
• These single-stranded RNA molecules are approximately
21 to 23 nucleotides in length and are processed from
primary transcripts known as pri-miRNA into short
stem-loop structures, pre-miRNA, and finally to
functional miRNA.
• Mature miRNA molecules are partially complementary
to one or more messenger RNA (mRNA) molecules and
function to downregulate gene expression.
• miRNAs are thought to affect the expression of
critical proteins within the cell, such as cytokines,
growth factors, transcription factors, etc.
• The expression profiles of miRNAs are frequently
altered in tumors.
• When miRNA’s targets are oncogenes, their loss of
function results in increased target gene expression.
• Conversely, overexpression of certain miRNAs may
decrease the levels of protein products of target
tumor suppressor genes.
• Therefore, miRNAs behave as oncogenes and tumor
suppressor genes.
II. MOLECULAR BASIS OF CANCER
• Cancer is a stepwise process. Often, several
genetic alterations must occur at specific sites
before malignant transformation is seen in
most adult cancers.
• Cancers of childhood appear to require fewer
mutations before manifestation of overt
cancer.
• Rare inherited mutations can pre-dispose
individuals to cancer at one or more sites. This
type of mutation is present virtually in all
somatic cells of the body.
A. Growth regulation
• Normal cells respond to a complex set of
biochemical signals, which allow them to
develop, grow, differentiate, or die.
• Cancer results when any cell is freed from
these types of restrictions and the resultant
abnormal progeny of cells are allowed to
proliferate.
B. Cancer genesis—a multistep process
• Mutations in the key genes have to
accumulate over time to create a progeny of
cells that have lost most control over growth.
• Each individual mutation contributes in
some way to eventually producing the
malignant state.
• The accumulation of these mutations spans
several years Several years and explains why
cancers take a long time to develop in
humans.
• Both exogenous (environmental insults) and
endogenous (carcinogenic products generated
by cellular reactions) processes may damage
DNA.
• DNA damage that goes unrepaired may lead to
mutations during mitosis.
• Increased errors during DNA replication or a
decreased efficiency of DNA repair may favor
increased frequency of genetic mutations
• Cells become cancerous when mutations occur
in proto-oncogenes and tumor suppressor
genes.
Colon cancer progression
• Cancer cells are genetically unstable and specific
genes are responsible for this instability.
• About 200 oncogenes and 170 tumor suppressor
genes identified
• Additional genes that aid in breaking down
basement membranes are also important for
oncogenesis
• Certain combinations of mutant genes were found
in distinct cancers and also different types of cancer
from the same tissue
• From these observations came different theories of
cancer formation
1. Clonal
evolution model
• Initial damage (a genetic mutation) occurs in a
single cell, giving it a selective growth advantage and
time to outnumber neighboring cells.
• Within this clonal population, a single cell may
acquire a second mutation, providing an additional
growth advantage and allowing it to expand and
become the predominant cell type.
• Repeated cycles followed by clonal expansion
eventually lead to a fully developed malignant
tumor.
• Accumulated mutations within key genes trigger a
single transformed cell to eventually develop into a
malignant tumor
Theory of clonal evolution
2. Hallmarks of cancer
According to this theory, oncogenesis requires
cells to
• Acquire self-sufficiency of growth signals
• Become insensitive to growth inhibitory
signals
• Evade apoptosis
• Acquire limitless replicative potential, and
• Sustain angiogenesis
• According to this model, the type of genetic
insult may vary with different cancers.
• All cancers, however, should acquire
damage to these different classes of genes
until a cell loses a critical number of growth
control mechanisms and initiates a tumor.
3. Stem cell theory of cancer
• Tumors contain cancer stem cells with
indefinite proliferative potential
• Cancer stem cells are self-renewing and
responsible for all components of a
heterogeneous tumor
• These tumor-initiating cells tend to be drug
resistant and to express markers typical of
stem cells
• Despite the small number of cancer stem cells,
they may be responsible for tumor recurrence
years after treatment.
D. Tumor progression
• Cancer cells gain metastatic abilities as they
evolve. Among these gene products that
allow breakdown of tissue structure and
invade basement membrane  migration
to other sites
• As tumors accumulate in cellular mass they
induce growth of blood vessels
(angiogenesis) to supply the growing tumor
with adequate nutrition and oxygen
Stem cell theory
of cancer
IV. Inherited mutations of cancer genes
• Number of individuals with inherited
predisposition is low compared total
number of human cancers
• Risk for cancer is several-fold higher in an
individual carrying a mutation in the cancer
causing gene
A. Inherited mutations mostly affect
tumor suppressor genes
• A large % of genes mutated in familial
cancers are due to tumor suppressor gene
• Mutation in proto-oncogenes during
development may not be compatible with
life.
Examples of familial cancer syndromes
Inherited mutations and cancer risk
• Cancer risk in individuals carrying a
mutation in a cancer-causing gene is several
fold greater, because the presence of the
mutation in every cell in their bodies makes
it highly likely for other mutations to occur
V. Mutations in drug-metabolizing
enzymes and cancer susceptibility
• Environmental chemicals may be classified as genotoxic
or non-genotoxic.
• Genotoxic chemicals interact with DNA, causing
mutations in critical genes
• Non-genotoxic (carcinogens) mechanisms differ
depending on nature of compound
• Chemical carcinogenesis is a multistep process.
• Chemicals that have no carcinogenic potential but
greatly enhance tumor development when exposed to
them for long periods of time mediate tumor promotion
• In terms of lifestyle, exogenous hormones, high-fat diet
etc. are known to promote cancer and therefore can be
an important determinant of cancer risk.
Chemical carcinogenesis
• While genetic predisposition, ethnicity, age, gender, and,
to some extent, health and nutritional impairment are
cancer susceptibility factors, recent studies are showing
polymorphisms in certain drug-metabolizing enzymes to
be associated with this inter-individual variation.
• Variations in the expression or form of the drugmetabolizing genes, such as cytochrome P450,
glutathione transferase, and N-acetyl transferase genes,
strongly influence individual biologic response to
carcinogens.
• While inheritance of cancer-causing genes will increase
the cancer risk, its occurrence in the population is low.
• On the other hand, the carcinogen-metabolizing
enzymes exist in different forms within the population at
a high rate and will increase the cancer risk in some
individuals carrying the form that allows activation of
certain carcinogens.
Chapter Summary
• Cancer is a multistep process.
• There are several characteristic features that a cell
has to attain before it undergoes neoplastic
transformation.
• Protooncogenes are normal counterparts of
oncogenes and usually have a role in growth
regulation.
• Tumor suppressor genes normally restrain growth.
• Protooncogenes undergo mutations that cause them
to be overactive or function without regulation.
• Tumor suppressor genes lose function when
mutated
• Oncogenes are dominant in action and tumor
suppressor genes are recessive
• Mutation in DNA repair genes can cause cancer
• Inherited predisposition to cancer accounts for 5-10% of
all human cancers
• Lifestyle factors influence cancer risk in the general
population
• Polymorphism in drug-metabolizing enzymes explains
cancer susceptibility in the general population
• Germ line mutations in cancer-causing genes occur
infrequently
• Polymorphism in drug-metabolizing enzymes occurs
more frequently
• Mutations in p53 gene are the most common cancerassociated mutations and its function underscores its
importance in the prevention of cancer