Carcinogenesis Professor Dr Nor Hayati Othman Pathology

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Carcinogenesis

• Professor Dr Nor Hayati Othman
• Pathology Department

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Carcinogenesis Overview

• Neoplasia Definitions
• Hypotheses of the Origin of Neoplasia
• Agents Causing Neoplasia

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Carcinogenesis Neoplasia

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

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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

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Carcinogenesis Overview

• Hypotheses of the Origin of Neoplasia
• Oncogenes and Tumor Suppresor Genes
• Viral Oncogene Hypothesis
• Epigenetic Hypothesis
• Failure of Immune Surveillance
• Agents Causing Neoplasia

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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

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Carcinogenesis Hypotheses of the Origin of
Neoplasia

• Multiple Hits and Multiple Factors
• Knudson proposed that carcinogenesis requires 2
  hits
• 1st event initiation
• Carcinogen initiator
• 2nd event promotion
• Agent promoter
• Multiple hits occur 5 or more
• 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

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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

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NORMAL CELL
Growth factor Growth factor receptor
cytoplasm
Signal transduction
Activation of transcription
nucleus
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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

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How does proto-oncogene get activated?

• point mutation
• translocation
• gene amplification

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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
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NEOPLASTIC CELLS
Increased In growth factor receptors
Increased In growth factor
Increased in signal transduction
Increase in activation of transcription
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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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Carcinogenesis Agents Causing Neoplasm

• Nuclear Fallout
• Hiroshima, Nagasaki (atomic blasts)
• Marshall islands (atmospheric testing of nuclear
  divide containing radioactive iodine)
• Chernobyl, 1986

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Carcinogenesis Agents Causing Neoplasm

• 3 Viral Oncogenesis
• Types
• Oncogenic RNA Viruses
• Oncogenic DNA Viruses
• Mode of Oncogenesis
• RNA Virus
• DNA Virus

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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

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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

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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

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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

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Carcinogenesis Agents Causing Neoplasm

• 6 - Genetic Oncogenesis (Role of Inheritance)
• Types
• Mendelian inheritance
• Polygenic inheritance
• Association with inherited diseases
• Mendelian Inheritance
• Dominant
• Recessive

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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

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Carcinogenesis Agents Causing Neoplasm

• Polygenic Inheritance
• Neoplasms occuring in related individuals more
  often than expected on the basis of chance
• Breast CA
• Colon CA

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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

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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

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Pathogenesis
Acquired environmental factors chemicals
,radiation ,viruses
Genetic factors
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