carcinogen es is 22

7/27/2019 Carcinogen Es is 22

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CarcinogenesisProfessor Dr Nor Hayati Othman

Pathology Department


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CarcinogenesisOverview

NeoplasiaDefinitions

Hypotheses of the Origin of Neoplasia

Agents Causing Neoplasia


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CarcinogenesisNeoplasia

NeoplasiaLatin, new growth

Cancercrab

Rupert Willis, 1950s


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Carcinogenesis - Overview

Neoplasia is an abnormality of cell growthand 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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1. Oncogenes and Tumor Suppresor Genes

2.

Viral Oncogene Hypothesis3. Epigenetic Hypothesis

4. Failure of Immune Surveillance



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CarcinogenesisHypotheses 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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Multiple Hits and Multiple Factors Knudson proposed that carcinogenesis requires 2

hits 1steventinitiation

Carcinogen = initiator

2ndeventpromotion

Agent = promoter

Multiple hits occur5 or more

Each hit produces a change in the genome which istransmitted 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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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 thatdown-regulate the cell cycle P53

Rb


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NORMAL CELLGrowth factorGrowth factor receptor

Signal transduction

Activation oftranscription

cytoplasm

nucleus


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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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point mutation

translocation

gene amplification

How does proto-oncogene

get activated?


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Relationship between gene products ofproto oncogene

Growth factors eg IGFGrowth factor receptorsEg erb-2, ret

Signal transducingfactorsEg cytoplasmic

kinases

DNA bindingproteins

concerned withtranscription

cell cycle

proteins egcyclin D


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NEOPLASTIC CELLS

Increased

In growthfactor

Increased

In growthfactorreceptors

Increased in

signaltransduction

Increase inactivation oftranscription


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2 Viral Oncogene Hypothesis

RNA Retrovirusproduces 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-oncsequence by recombinant mechanism fromanimal cells

DNA virus Do not contain viral oncogenes

Act by blocking suppressor gene products

ExamplesHPV, EBV,HBV


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3 Epigenetic Hypothesis

Changes in the regulation of geneexpression rather than in the geneticapparatus

Pattern of gene expressionsresponsible for tissue differentiation

(ie. epigenetic mechanism) arethought to be heritable


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4 Failure of Immune Surveillance

Concepts

Neoplastic changes frequently occur incells

Altered DNA result in production ofneoantigens & tumor-associatedantigens

Immune response (cytotoxic) toneoantigens as foreign antigens

Neoplastic cells escaping recognition

and destruction become clinical cancers


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yawwwwwwwn!


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NeoplasiaDefinitions



Chemical Oncogensis

Radiation Oncogenesis

Viral Oncogenesis

Nutritional OncogenesisHormonal Oncogenesis

Genetic Oncogenesis


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CarcinogenesisAgents Causing Neoplasm

Carcinogenssubstances known tocause cancer or produces an increasein incidence of cancer in animals or

humansCause of most cancers is unknown

Most cancers are probably multifactorial inorigin

Known carcinogenic agents constitute asmall percentage of cases

Unidentified environmental agents

probably play a role in 95% of cancers


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1 - Chemical Carcinogenesis

Types

Proximate or direct-acting : act locallywithout metabolic change

Indirect acting: carcinogenic only after

being metabolised into active

compounds (procarcinogen ultimatecarcinogen)


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Mode of carcinogenesis Inducing changes in DNAeg. Base alkylation,

deletion, breakage, cross-linkage

Epigenetic mechanisms

Synergistic action with viruses

Promoter for other carcinogens

Difficulties in identifying carcinogen

Numerous industrial, agricultural, householdchemicals present in low levels

Exposed to large number of chemicals in alifetime

Long lag phase


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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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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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X-ray radiation

Earlier use of X-rays caused skincancer, leukemia and papillary thyroid

CARadiotherapy causes raditation-induced

malignancy 10-30 yrs laterusuallysarcomas

Diagnostic X-rays are considered tohave no increased risk except inabdominal x-rays which increaseincidence of leukemia in the fetus


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Radioisotopes

Osteosarcoma common among factory workers

who use radium-containing paints

Radioactive mineral mining in Europe and USAassociated with lung cancer

Thorium increases risk of liver cancer

hepatocellular, angiosarcoma,

cholangiocarcinoma Radioactive iodineincreased risk of cancer

15-25 years later


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Nuclear Fallout

Hiroshima, Nagasaki (atomic blasts)

Marshall islands (atmospheric testing of nuclear

divide containing radioactive iodine) Chernobyl, 1986


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3 Viral Oncogenesis

Types

Oncogenic RNA VirusesOncogenic DNA Viruses

Mode of Oncogenesis

RNA VirusDNA Virus


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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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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, awaitingconfirmation Beta-carotene

Vitamin C, E

Selenium


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5 Hormonal Oncogenesis

Types

Induction of Neoplasms by Hormones

Dependence of Neoplasms on Hormones

Hormones inducing Neoplasms

Estrogenbreast ca

Diethylstilbestrol (DES)vaginal and uterineca


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Hormonal Dependence of Neoplasms

Neoplasm not caused by hormones but dependon 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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6 - Genetic Oncogenesis (Role ofInheritance)

Types

Mendelian inheritance Polygenic inheritance

Association with inherited diseases

Mendelian Inheritance

Dominant Recessive


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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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Polygenic Inheritance

Neoplasms occuring in related

individuals more often than expected on

the basis of chance Breast CA

Colon CA


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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 iscomplex

it is a genetic disease- either

acquired genetic abnormality orinherited genetic abnormality

It arises when several mutations

accumulate within genome


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conclusionAdded insults from the

environmental exposures tocarcinogens : chemicals,

radiation, virusesGrowth autonomy from

activation of growth factors or by

suppression of tumoursuppressor genes


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Acquired environmental factorschemicals ,radiation ,viruses

Changes in genomeof somatic cells

Activation of growthpromoting oncogenes

Inactivation of cancersupressor genes

Expression all altered gene productsand loss of regular gene products

MALIGNANT NEOPLSM

Genetic factor

carcinogen es is 22

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