carcinogenesis cqrcinogenic agents 2010

7/29/2019 carcinogenesis cqrcinogenic agents 2010

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Carcinogenesis,

Carcinogenic Agentsand

Their Cellular Interaction


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Carcinogenesis

A large number of agents cause geneticdamage and induce neoplastic

transformation of cells Chemical Carcinogens

Radiant energy

Oncogenic viruses and some othermicrobes


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Experimental model: Normal Cells

INITIATION

PROMOTION

Cancer Cells

Chemical Carcinogenesis


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Chemical Carcinogenesis is a

Multistep ProcessStages of Chemical Carcinogenesis

Initiation, likely represents a mutation in a single cell

Promotion, follows initiation and reflects the clonalexpansion of the initiated cells, and maintain it

Progression, is the stage in which growth becomeautonomous, by this time, sufficient mutations haveaccumulated to immortalize cells

Cancer, the end result of the entire sequence


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Initiation-promotion scheme


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INITIATION

Initiator alone is not sufficient for tumorformation (Group 1)

Initiation results from exposure of cells to an

appropriate dose of initiator (carcinogenicagents)

Initiation irreversible mutation (DNAdamage) memory months later

+promoter tumor (Group 2&3)


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PROMOTION

promoter is non-tumorigenic by itself

Induce tumors in initiated cells (Group 5)

When promoter is applied before initiator, no

tumor developed (Group 4) When the time between multiple application is

extended the effect of promoter is reversible

tumors failed to develop (Group 6)


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Initiation

&

Promotion


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Initiation&

promotion


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Events in ChemicalCarcinogenesis


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Major Chemical Carcinogen

Direct-acting Carcinogens

Alkylating Agents

Acylating agents

Procarcinogen that Require Metabolic activation Polycyclic & Heterocyclic Aromatic Hydrocarbons

Aromatic Amines, Amides, Azo Dyes

Natural Plant and Microbial Products Others


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Chemical Carcinogens are MostlyMutagen

A mutagen is an agent that can permanently alter thegenetic constitution of a cell

A mutagen is not necesserily a carcinogen

Cell culture good method to study:

- mutation, assays of mutagenicity

- unscheduled DNA synthesis

- DNA strand breaks- Screening for carcinogenic potential of chemicals


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Initiation of Carcinogenesis

1. Direct acting compound do not require chemicaltransformation for their carcinogenicity

2. Indirect acting compound / procarcinogen, requiremetabolic conversion in vivo to produce ultimatecarcinogen

Property in common:

= They are highly reactive electrophiles that can reactwith nucleophilic sites in the cell electrophilic

reaction sub-lethal damage to DNA

= Molecularfingerprint


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Carcinogen tumor types (fingerprinting)


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Promoters

Promoters: phorbol esters, hormone, phenols,drugs

Not mutagenic how do they contribute totumorigenesis study of TPA (tetradecanoyl

phorbol-13 acetate) TPA: - phorbol esters

- powerful activator for protein kinase C, an

enzyme that phophorylates several

substrates involved in signal transductionpathways


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Tumor Promotion

Application of promoter leads to proliferation andclonal expansion of initiated (mutated) cells

Initiated cells respond differently to promoters thando normal cells and hence expand selectively

Tumor promotion includes multiple steps:

- Proliferation of preneoplastic cells

- Malignant conversion

- Tumor progression


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AflatoxinCarcinogenesis


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Metal Carcinogen Metals/metal compounds can induce cancer, but the

mechanism is unkown Divalent metal cations (Ni++, Pb++, Cd++, Co++, Be++) are

electrophilic possible to react with macromolecules

Metal ions react with guanin and phosphate group of

DNA Metal ions can depolymerize polynucleotides

Bind to purine and pyrimidine bases through covalentbinding

Most metal-induced cancers occur in an occupationalsetting

How do they occur in vivo is not known


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Radiation Carcinogenesis

Transform all kind of cells in vitro and induce neoplasms

in vivo, in human & experimental animal

UV light skin cancer

Ionizing radiation of medical, occupational, and bomb of

origins produce a variety of malignant neoplasms

The effect of UV light is somewhat differ from those ofionizing radiation


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UV

UV effects on cells inhibition of cell division,inactivation of enzymes, induction of mutation, and

killing the cells

UV type:

- UVA (320 400 nm): non-mutagenic- UVB (280 320 nm): mutagen, not filtered by ozone

- UVC (200 280 nm): mutagen, filtered by ozone

Type of cancer results are skin cancers: SCC, BCC,

melanoma UVB also causes mutation in oncogenes (ras) and

tumor suppressor genes (p53)


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The carcinogenicity of UVB is attributed to itsformation of pyrimidine dimers in DNA

This DNA damage is repaired by NER(nucleotide excision repair)

1. Recognition of the DNA lesion

2. Incision of the damage strand on both sitesof the

lesion

3. Removal of the damage nucleotide

4. Synthesis of a nucleotide patch5. Synthesis of its ligation


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The Formation of

Pyrimidine Dimers of the DNA May between thymine & thymine, thymine &

cytosine, cytosine pairs alone leads to

cyclobutane ring distort the phosphodiesterbackbone of the double helix in the region of

each dimer

Unless repaired by NER genomic mutation

produced by UV radiation is mutagenic and

carcinogenic


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NER (nucleotide excision repair)

This process needs at least the product of 20

genes

Postulation: excessive sun exposure capacity

of NER pathway in overwhelmed some DNAdamage remains unrepaired large

transcription errors cancer

Xeroderma pigmentosum (photosensitivity, 200-

fold risk of ckin cancer) has several mutated

genes involved in NER


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Ionizing Radiation

Electromagnetic radiation

- X-rays and gamma rays

Particulate radiation

- particles, particles, proton,

neutron


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Hierarchy of Vulnerability

1. Leukemia

2. Thyroid

3. Breast, lung, salivary gland(intermediate)

4. Skin, bone, gastrointestinal tract

(relatively resistant)


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Viral & Microbial Oncogenesis

Virus: DNA & RNA (retrovirus/oncorna virus),some carry oncogene, some dont

Microbial Helicobacter pylori


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Virus DNA

A Cytopathic Virus The virus is integrated into the host

genom cell transformation

The integrated genes by the virus whichproduce cell transformation expressed

inside transformed cells

The important viruses: HPV, EBV, HBV,KSHV


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HPV (Human Papilloma Virus)

High risk: strain 16, 18, and the less found arestrain 31, 33, 35, dan 51 invasive SCC (85%)with the tumor precursors: severe dysplasia andin situ Ca

Low risk: the dominant are 6 & 11 genital wartwith low malignant potential

Strain 1, 2, 4, 7 papilloma

Oncoprotein from type 16 & 18 can interact

(binding) with p53 and pRb with high affinitycell transformation


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Effect of HPV Protein E6 & E7 onthe Cell Cycle


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EBV(Epstein Barr virus) Has role in the pathogenesis tumor: lymphoma

Burkitt (African form), B cell lymphoma in personwith immunosuppression, Hodgkin lymphoma,and NPC

EBV infects oropharynx epithelial and the B cell

(via receptor CD21) cell immortalization Oncoprotein: LMP-1 inhibit apoptosis by up-

regulating bcl-2, and activates growth-promotingpathways

EBNA-2: transactivation several host genes(cyclin D and srcfamily members), and activatetranscription of LMP-1


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Virus DNA onkogenik

EBV

Translocation of MYC(mutation)

Limfoma Burkitt


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HBV(Hepatitis B Virus) HBV infection increases the risk of the

development of HCC 200X

The virus is integrated into the liver cell genom, but

not developing oncoprotein no consistent pattern

of oncogenesis maybe the effects are indirect:1. Chronic inflammation cirrhosis regenerative

hyperplasia

2. HBV codes the protein HBx

destroy normaldevelopment control

3. HBx binding to p53 inactivated suppresion


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KSHV (Kaposi Sarcoma Herpes Virus)

Ther member of herpes virus family

Etiological factor etiology for Kaposi sarcomaespecially in the imunodefficient individuals(AIDS)

The basic pathogenesis is multifactorial:

1. Severe T cell imunity defect

2. Disregulation of B cell and monocyte

3. Multiple known viral infection (HHV type8, EBV, HPV), and unknown virus


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Retrovirus: HTLV-1

Human T-cell Leukemia Virus Type 1

the onethat recognized oncogenic to human (a lot in

animal)

The tendency of infection to limfocyte CD4+

Sexual intercourse infection, blood, breast-

feeding

Leukemia: only 1% of all infected person after

latent period of 20-30 years


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Retrovirus

HTLV-1

Is a lymphotrophic agent


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Helicobacter pylori

Carcinoma

Lymphoma

Strong relationship

Epidemiologic study:

- Detection of HP infection in the

great majority of gastric lymphoma

- Treatment of HP infection with anti-

biotics results in regression of the

lymphoma in most cases

Infection

Only 20-30% : ulcers


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Helicobacter pylori

The strain causing disease contain pathogenic islandcontaining CagA (cytotoxin associated gene A) andsecretory system injects the CagA protein into thehost cells

Gene associated with virulence: VacA (encodevacuolated toxin that causes apoptosis)

The infection is associated with adenocarcinomas of the

intestinal type (sequence: chronic gastritis multifocal

atrophy with lower gastric acid secretion intestinal

metaplasia dysplasia carcinoma)


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Gastric Lymphoma(mucosal associated lymphoid tissue / MALT MALTOMA)

-The B-cell that give rise to this tumor normally

reside in the marginal zone marginal zonelymphoma

-Infection lymphoid infiltrates B-cells actively

proliferate may acquire genetic abnormalities

such as 11;18 translocation

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