Carcinogenic Agents

and
Their Cellular Interaction

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Carcinogenesis
A large number of agents cause genetic
damage and induce neoplastic
transformation of cells
Chemical Carcinogens
Radiant energy
Oncogenic viruses and some other
microbes
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Chemical Carcinogenesis
Experimental model:

Normal Cells

INITIATION

PROMOTION
Cancer Cells
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Chemical Carcinogenesis is a
Multistep Process
Stages of Chemical Carcinogenesis
Initiation, likely represents a mutation in a single cell
Promotion, follows initiation and reflects the clonal
expansion of the initiated cells, and maintain it
Progression, is the stage in which growth become
autonomous, by this time, sufficient mutations have
accumulated 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 tumor
formation (Group 1)
Initiation results from exposure of cells
to an appropriate dose of initiator
(carcinogenic agents)
Initiation irreversible mutation (DNA
damage) 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 Chemical
Carcinogenesis

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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 Mostly

Mutagen
A mutagen is an agent that can permanently alter the
genetic 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
chemical transformation for their
carcinogenicity
2. Indirect acting compound / procarcinogen, require
metabolic conversion in vivo to produce
ultimate carcinogen
Property in common:
= They are highly reactive electrophiles that
can react with nucleophilic sites in the cell
electrophilic reaction sub-lethal damage to
DNA
= Molecular fingerprint
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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 to
tumorigenesis study of TPA (tetradecanoyl
phorbol-13 acetate)
TPA: - phorbol esters
- powerful activator for protein kinase C, an
enzyme that phophrylates several
substrates involved in signal transduction
pathways
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Tumor Promotion
Application of promoter leads to proliferation and
clonal expansion of initiated (mutated) cells
Initiated cells respond differently to promoters than
do normal cells and hence expand selectively
Tumor promotion includes multiple steps:

- Proliferation of preneoplastic cells

- Malignant conversion
- Tumor progression

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Aflatoxin
Carcinogenesis

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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 covalent
binding
Most metal-induced cancers occur in an occupational
setting
How do they occur in vivo is not known
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Kanker - Pekerjaan
Agen

Kanker

Pekerjaan

Arsen

Paru, kulit,
hemangiosarkoma

Logam, alloy, semikonduktor,

obat, herbisida, fungisida,dll.

Asbes

Paru, mesotelioma,
GI tract

Macam-macam

Benzene

Leukemia, hodgkin

Minyak ringan pelarut: cat,

lem, bahan pembersih, detergen

Berilium

Paru

Fuels, pengeras metal alloy

Cadmium

Prostat

Bateri, cat kuning/fosfor, coating

Chromium

Paru

Metal alloy, cat, presevatif

Ethylen oxide Leukemia

Bahan bakar roket,

Nikel

Hidung, paru

Alloy, plating, bateri, las

Radon

Paru

Radioaktif, tambang

Vinyl chloride Angiosarkoma, hati

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Refrigerant, polimer vinil, lem

plastik
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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 of
ionizing 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 its

formation 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 sites of
the
lesion
3. Removal of the damage nucleotide
4. Synthesis of a nucleotide patch
5. 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 phosphodiester
backbone 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 DNA damage 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 which
produce 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 are
strain 31, 33, 35, dan 51 invasive SCC (85%)
with the tumor precursors: severe dysplasia and
in situ Ca
Low risk: the dominant are 6 & 11 genital wart
with low malignant potential
Strain 1, 2, 4, 7 papilloma
Oncoprotein from type 16 & 18 can interact
(binding) with p53 and pRb with high affinity
cell transformation

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Effect of HPV Protein E6 & E7 on

the Cell Cycle

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EBV(Epstein Barr virus)

Has role in the pathogenesis tumor: lymphoma
Burkitt (African form), B cell lymphoma in person
with immunosuppression, Hodgkin lymphoma,
and NPC
EBV infects oropharynx epithelial and the B cell
(via receptor CD21) cell immortalization
Onkoprotein: LMP-1 inhibit apoptosis by upregulating bcl-2, and activates growth-promoting
pathways
EBNA-2: transactivation several host genes
(cyclin D and src family members), and activate
transcription 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 normal
development 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 sarcoma
especially 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 type
8, EBV, HPV), and unknown virus
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Retrovirus: HTLV-1
Human T-cell Leukemia Virus Type 1 the one
that recognized oncogenic to human (a lot in
animal)
The tendency of infection to limfocyte CD4+
Sexual intercourse infection, blood, breastfeeding
Leukemia: only 1% of all infected person after
latent period of 20-30 years

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Retrovirus

HTLV-1
Is a lymphotropic agent

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Helicobacter pylori
Infection
Only 20-30% : ulcers

Strong relationship

Epidemiologic study:
- Detection of HP infection in the
great majority of gastric lymphoma

Carcinoma

- Treatment of HP infection with antibiotics results in regression of the

lymphoma in most cases

Lymphoma
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Helicobacter pylori
The strain causing disease contain pathogenic island
containing CagA (cytotoxin associated gene A) and
secretory system injects the CagA protein into the
host cells
Gene associated with virulence: VacA (encode
vacuolated 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 zone
lymphoma
-Infection lymphoid infiltrates B-cells actively
proliferate may acquire genetic abnormalities
such as 11;18 translocation

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