Carcinogenesis

Carcinogenesis
Irsyad Ediwan, dr.
Carcinogenesis Overview
Neoplasia
Definitions
Hypotheses of the Origin of Neoplasia
Agents Causing Neoplasia
Carcinogenesis Neoplasia
Neoplasia
Latin, new growth

Cancer crab
Rupert Willis, 1950s
Carcinogenesis - Overview
Neoplasia is an abnormality of cell growth
and multiplication characterised by
At cellular level
Excessive cellular proliferation

Uncoordinated growth
Tissue infiltration
At molecular level
Disorder of growth regulatory genes

Develops in a multistep fashion

1.
2.
3.
4.
Oncogenes and Tumor Suppresor Genes

Viral Oncogene Hypothesis
Epigenetic Hypothesis
Failure of Immune Surveillance
Carcinogenesis
Origin
of Neoplasia two general types
Monoclonal
Initial neoplastic change affects a single cell
Field
origin
Carcinogen acts on large number of cells

producing field of potentially neoplastic cells
Carcinogenesis
Multiple Hits and Multiple Factors
Knudson proposed that carcinogenesis requires 2 hits
1st event initiation
2nd event promotion
Agent = promoter
Multiple hits occur 5 or more
Carcinogen = initiator
Each hit produces a change in the genome which is transmitted

to its progeny (ie. clone)
Lag period
Time between exposure (first hit) and development of clinically

apparent cancer
Altered cell shows no abnormality during lag period
Carcinogenesis
1 Oncogenes and Tumor Suppresor Genes
Two categories of cell regulatory genes
Proto-oncogenes code for
Proto-oncogenes (cellular oncogene, c-onc)

Tumor suppressor gene
Growth factors
Receptors
Signal-relay or transduction factors
Tumor suppressor genes code for factors that downregulate the cell cycle
P53
Rb
NORMAL CELL
Growth factor
Growth factor recepto
cytoplasm
Signal transduction
nucleus
Activation of
transcription
Carcinogenesis
1
Oncogenes and Tumor Suppresor

Genes
Gene
Activation and Inactivation
Proto-oncogene is activated or tumor

suppressor gene is inactivated
normal growth regulation is diverted into
oncogenesis
Activated proto-oncogene = activated
oncogene, mutant oncogene, cellular oncogene
How does proto-oncogene

get activated?
point
mutation
translocation
gene amplification
Relationship between gene

products of proto oncogene
Growth factors eg IGF
Growth factor receptors
Eg erb-2, ret
Signal transducing
factors
Eg cytoplasmic
kinases
cell cycle
proteins eg
cyclin D
DNA binding
proteins
concerned
with
NEOPLASTIC CELLS
Increase
d
In growth
factor
Increased
In growth
factor
receptors
Increased
in signal
transductio
n
Increase in
activation
of
transcripti
on
Carcinogenesis
2
Viral Oncogene Hypothesis
RNA
Retrovirus produces DNA provirus
DNA provirus containing viral oncogene (v-onc) is

introduced, or
DNA provirus without v-onc is inserted adjacent to c-onc in
host cell DNA
RNA viruses is thought to have acquired v-onc sequence
by recombinant mechanism from animal cells
DNA
virus
Do not contain viral oncogenes

Act by blocking suppressor gene products
Examples HPV, EBV,HBV
Carcinogenesis
3
Epigenetic Hypothesis
Changes
in the regulation of gene

expression rather than in the genetic
apparatus
Pattern of gene expressions
responsible for tissue differentiation
(ie. epigenetic mechanism) are
thought to be heritable
Carcinogenesis
4
Failure of Immune Surveillance
Concepts
Neoplastic changes frequently occur in cells

Altered DNA result in production of
neoantigens & tumor-associated antigens
Immune response (cytotoxic) to
neoantigens as foreign antigens
Neoplastic cells escaping recognition and
destruction become clinical cancers
Feeling sleepy
yawwwwwwwn!
Neoplasia
Definitions
Chemical
Oncogensis
Radiation Oncogenesis
Viral Oncogenesis
Nutritional Oncogenesis
Hormonal Oncogenesis
Genetic Oncogenesis
Carcinogenesis
Agents Causing Neoplasm
Carcinogens
substances known to cause

cancer or produces an increase in
incidence of cancer in animals or humans
Cause
of most cancers is unknown

Most cancers are probably multifactorial in
origin
Known carcinogenic agents constitute a small
percentage of cases
Unidentified environmental agents probably
play a role in 95% of cancers
Carcinogenesis
1
- Chemical Carcinogenesis
Types
Proximate or direct-acting : act locally

without metabolic change
Indirect acting : carcinogenic only after
being metabolised into active
compounds (procarcinogen ultimate
carcinogen)
Carcinogenesis
Mode
of carcinogenesis
Inducing changes in DNA eg. Base alkylation,

deletion, breakage, cross-linkage
Epigenetic mechanisms
Synergistic action with viruses
Promoter for other carcinogens
Difficulties
in identifying carcinogen
Numerous industrial, agricultural, household

chemicals present in low levels
Exposed to large number of chemicals in a lifetime
Long lag phase
Carcinogenesis
2
Radiation Oncogenesis
Types
of oncogenic radiation
Ultraviolet
X-ray
Radioisotopes
Nuclear Fallout
Mode
of oncogenesis
Direct effect on DNA

Activation of cellular oncogenes
Carcinogenesis
UV
Radiation
Solar UV radiation associated with skin cancers

squamous CA, basal cell CA, malignant
melanoma
Fair-skinned and elderly are susceptible
UV light is believed to induce cross-linkages
between DNA molecules and CA occurs when
repair mechanisms are not efficient
Carcinogenesis
X-ray
radiation
Earlier use of X-rays caused skin cancer,

leukemia and papillary thyroid CA
Radiotherapy causes raditation-induced
malignancy 10-30 yrs later usually
sarcomas
Diagnostic X-rays are considered to have
no increased risk except in abdominal xrays which increase incidence of leukemia
in the fetus
Carcinogenesis
Radioisotopes
Osteosarcoma common among factory workers

who use radium-containing paints
Radioactive mineral mining in Europe and USA
associated with lung cancer
Thorium increases risk of liver cancer
hepatocellular, angiosarcoma,
cholangiocarcinoma
Radioactive iodine increased risk of cancer
15-25 years later
Carcinogenesis
Nuclear
Fallout
Hiroshima, Nagasaki (atomic blasts)

Marshall islands (atmospheric testing of nuclear
divide containing radioactive iodine)
Chernobyl, 1986
Carcinogenesis
3
Viral Oncogenesis
Types
Oncogenic RNA Viruses
Oncogenic DNA Viruses
Mode
of Oncogenesis
RNA Virus
DNA Virus
Carcinogenesis
Detection
of viral genome
Identification of viral-specific nucleic acid

sequences by hybridisation with DNA/RNA
probes
Recognition of virus-specific antigens on
infected cells
Detection of virus-specific mRNA
Carcinogenesis
4 Nutritional Oncogenesis
Scant evidence linking cancer to diet except for known

chemical carcinogens
Some associations
Low-fiber diet and colonic CA

Fatty diet with breast ca
Betel leaves with oral ca
Protective agents ?antioxidant effect, awaiting

confirmation
Beta-carotene
Vitamin C, E
Selenium
Carcinogenesis
5
Hormonal Oncogenesis
Types
Induction of Neoplasms by Hormones

Dependence of Neoplasms on Hormones
Hormones
inducing Neoplasms
Estrogen breast ca
Diethylstilbestrol (DES) vaginal and uterine
ca
Carcinogenesis
Hormonal Dependence of Neoplasms

Neoplasm not caused by hormones but depend
on hormones for optimal growth
Neoplastic cells possess receptors for binding
hormone
Loss of hormonal stimulation slow but does not
halt growth
Examples
Prostate CA
Breast CA
Thyroid CA
Carcinogenesis
6 - Genetic Oncogenesis (Role of Inheritance)

Types
Mendelian inheritance
Polygenic inheritance
Association with inherited diseases
Mendelian
Inheritance
Dominant
Recessive
Carcinogenesis
Examples
Retinoblastoma
Wilms tumor
Others
Neurofibromatosis (type 1 von
Recklinghausens disease)
Multiple endocrine adenomatosis (MEN)
Familial polyposis coli
Nevoid basal cell carcinoma syndrome
Carcinogenesis
Polygenic
Inheritance
Neoplasms occuring in related

individuals more often than expected on
the basis of chance
Breast CA
Colon CA
Carcinogenesis
Association
with Inherited Diseases
Many inherited diseases are associated

with higher risk of neoplasia
Types :
Syndromes characterised by increased

chromosomal fragility
Syndromes of immunodeficiency
I am yawning!!
conclusion
Pathogenesis
of cancer is
complex
it is a genetic disease- either
acquired genetic abnormality or
inherited genetic abnormality
It arises when several mutations
accumulate within genome
conclusion
Added
insults from the

environmental exposures to
carcinogens : chemicals,
radiation, viruses
Growth autonomy from activation
of growth factors or by
suppression of tumour
suppressor genes
es
is
Pa
th
o
ge
n
Acquired environmental factors

chemicals ,radiation ,viruses
Genetic factor
Changes in genome
of somatic cells
Activation of growth Inactivation of cancer
promoting oncogenes
supressor genes
Expression all altered gene products

and loss of regular gene products
MALIGNANT NEOPLSM

Carcinogenesis

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Carcinogenesis

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Carcinogenesis

Irsyad Ediwan, dr.

Latin, new growth

Excessive cellular proliferation

Disorder of growth regulatory genes

Hypotheses of the Origin of Neoplasia

Oncogenes and Tumor Suppresor Genes

Agents Causing Neoplasia

of Neoplasia two general types

Initial neoplastic change affects a single cell

Carcinogen acts on large number of cells

Multiple Hits and Multiple Factors

Knudson proposed that carcinogenesis requires 2 hits

1st event initiation

2nd event promotion

Multiple hits occur 5 or more

Each hit produces a change in the genome which is transmitted

Time between exposure (first hit) and development of clinically

1 Oncogenes and Tumor Suppresor Genes

Two categories of cell regulatory genes

Proto-oncogenes code for

Proto-oncogenes (cellular oncogene, c-onc)

Oncogenes and Tumor Suppresor

Activation and Inactivation

Proto-oncogene is activated or tumor

How does proto-oncogene

Relationship between gene

Viral Oncogene Hypothesis

Retrovirus produces DNA provirus

DNA provirus containing viral oncogene (v-onc) is

Do not contain viral oncogenes

in the regulation of gene

Failure of Immune Surveillance

Neoplastic changes frequently occur in cells

substances known to cause

of most cancers is unknown

Proximate or direct-acting : act locally

Inducing changes in DNA eg. Base alkylation,

Numerous industrial, agricultural, household

Direct effect on DNA

Solar UV radiation associated with skin cancers

Earlier use of X-rays caused skin cancer,

Osteosarcoma common among factory workers

Hiroshima, Nagasaki (atomic blasts)

Identification of viral-specific nucleic acid

Scant evidence linking cancer to diet except for known

Low-fiber diet and colonic CA

Protective agents ?antioxidant effect, awaiting

Induction of Neoplasms by Hormones

Hormonal Dependence of Neoplasms

6 - Genetic Oncogenesis (Role of Inheritance)

Neoplasms occuring in related

with Inherited Diseases

Many inherited diseases are associated

Syndromes characterised by increased

insults from the

Acquired environmental factors

Expression all altered gene products

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