Carcinogenesis

Professor Dr Nor Hayati Othman Pathology Department

Carcinogenesis Overview
Definitions Hypotheses of the Origin of Neoplasia Agents Causing Neoplasia
Neoplasia

Carcinogenesis Neoplasia
Latin, new growth Cancer crab Rupert Willis, 1950s
Neoplasia

Carcinogenesis - Overview

Neoplasia is an abnormality of cell growth and multiplication characterised by At cellular level

Excessive cellular proliferation Uncoordinated growth Tissue infiltration Disorder of growth regulatory genes Develops in a multistep fashion

At molecular level

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

Carcinogen = initiator Agent = promoter

2nd event promotion

Multiple hits occur 5 or more

Each hit produces a change in the genome which is transmitted to its progeny (ie. clone) Time between exposure (first hit) and development of clinically apparent cancer Altered cell shows no abnormality during lag period

Lag period

Carcinogenesis
Hypotheses of the Origin of Neoplasia

1 Oncogenes and Tumor Suppresor Genes

Two categories of cell regulatory genes

Proto-oncogenes (cellular oncogene, c-onc) Tumor suppressor gene

Proto-oncogenes code for

Growth factors Receptors Signal-relay or transduction factors

Tumor suppressor genes code for factors that down-regulate the cell cycle

P53 Rb

NORMAL CELL
Growth factor Growth factor receptor

cytoplasm
Signal transduction Activation of transcription

nucleus

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

DNA binding proteins concerned with transcription

cell cycle proteins eg cyclin D

NEOPLASTIC CELLS

Increased In growth factor

Increased In growth factor receptors

Increased in signal transduction

Increase in activation of transcription

Carcinogenesis
Hypotheses of the Origin of Neoplasia
2

Viral Oncogene Hypothesis

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

RNA

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

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

Concepts

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Carcinogenesis Overview
Definitions Hypotheses of the Origin of Neoplasia Agents Causing Neoplasia
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
Proximate or direct-acting : act locally without metabolic change Indirect acting : carcinogenic only after being metabolised into active compounds (procarcinogen ultimate carcinogen)

Types

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
of oncogenic radiation
Ultraviolet X-ray Radioisotopes Nuclear Fallout

Types

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 x-rays 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
Induction of Neoplasms by Hormones Dependence of Neoplasms on Hormones

Types

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

Acquired environmental factors chemicals ,radiation ,viruses

Genetic factor

Changes in genome of somatic cells Activation of growth promoting oncogenes Inactivation of cancer supressor genes

Expression all altered gene products and loss of regular gene products

MALIGNANT NEOPLSM