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

Carcinogenesis Overview

Hypotheses of the Origin of Neoplasia

1.
2.
3.
4.

Oncogenes and Tumor Suppresor Genes

Viral Oncogene Hypothesis
Epigenetic Hypothesis
Failure of Immune Surveillance

Agents Causing Neoplasia

Carcinogenesis
Hypotheses of the Origin of Neoplasia
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
Hypotheses of the Origin of Neoplasia

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
Hypotheses of the Origin of Neoplasia

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
Hypotheses of the Origin of Neoplasia
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
Hypotheses of the Origin of Neoplasia
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
Hypotheses of the Origin of Neoplasia
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
Hypotheses of the Origin of Neoplasia
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

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Carcinogenesis Overview
Neoplasia

Definitions
Hypotheses of the Origin of Neoplasia
Agents Causing Neoplasia
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
Agents Causing Neoplasm
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
Agents Causing Neoplasm
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
Agents Causing Neoplasm
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
Agents Causing Neoplasm
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
Agents Causing Neoplasm
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
Agents Causing Neoplasm
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
Agents Causing Neoplasm
Nuclear

Fallout

Hiroshima, Nagasaki (atomic blasts)

Marshall islands (atmospheric testing of nuclear
divide containing radioactive iodine)
Chernobyl, 1986

Carcinogenesis
Agents Causing Neoplasm
3

Viral Oncogenesis
Types
Oncogenic RNA Viruses
Oncogenic DNA Viruses

Mode

of Oncogenesis

RNA Virus
DNA Virus

Carcinogenesis
Agents Causing Neoplasm
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
Agents Causing Neoplasm

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
Agents Causing Neoplasm
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
Agents Causing Neoplasm

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
Agents Causing Neoplasm

6 - Genetic Oncogenesis (Role of Inheritance)

Types
Mendelian inheritance
Polygenic inheritance
Association with inherited diseases

Mendelian

Inheritance

Dominant
Recessive

Carcinogenesis
Agents Causing Neoplasm

Examples
Retinoblastoma
Wilms tumor
Others
Neurofibromatosis (type 1 von
Recklinghausens disease)
Multiple endocrine adenomatosis (MEN)
Familial polyposis coli
Nevoid basal cell carcinoma syndrome

Carcinogenesis
Agents Causing Neoplasm
Polygenic

Inheritance

Neoplasms occuring in related

individuals more often than expected on
the basis of chance
Breast CA
Colon CA

Carcinogenesis
Agents Causing Neoplasm
Association

with Inherited Diseases

Many inherited diseases are associated

with higher risk of neoplasia
Types :

Syndromes characterised by increased

chromosomal fragility
Syndromes of immunodeficiency

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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