karsinogenesis - Repository Unand

BLOK 2.1
KARSINOGENESIS
dr ASWIYANTI ASRI,M.Si.Med,SpPA
Karsinogenesis
the process by which a normal cell is
transformed into a malignant cell
and repeatedly divides to become a
cancer.
Key Concepts
• Kanker berasal dari satu sel
• Kanker terjadi karena mutasi somatik
– Genetic change : mutasi DNA
– Epigenetic change : perubahan ekspresi gen tanpa
perubahan DNA
• Mutasi tunggal belum cukup untuk menyebabkan kanker
• Kanker berkembang dari aberasi ringan sel
– Insidens kanker paru meningkat 10-20 tahun sejak mulai
merokok
Key Concepts
• Karsinogen adalah mutagen yang mempunyai potensial untuk
berinteraksi dengan DNA.
• Bahan kimiawi yang dapat menginisiasi karsinogenesis disebut
karsinogen kimiawi
• Bahan kimia yang non-karsinogenik atau karsinogenik lemah
dapat meningkatkan efektivitas karsinogen kimiawi; bahan ini
disebut kokarsinogen.
• Kokarsinogen bekerja dengan mengubah uptake atau
metabolisme karsinogen oleh sel.
Non-lethal Genetic damage lies at the
center of carcinogenesis.
•
•
•
•
Loss/damage to suppressor genes,
Duplication of promotor genes
Loss/damage to Apoptosis genes
Loss/damage of DNA repair genes.
Istilah
•
•
•
•
•
•
Carcinogenesis: Pathogenesis of cancer
Carcinogen - agent causing cancer.
Oncogen - agent causing neoplasm.
Mutagen - agent causing mutation.
Oncogenes – genes causing cancer
p-onc, v-onc – Proto/viral/ - naming of
oncogenes.
• Karsinogen – bahan yang sudah diketahui
menyebabkan kanker atau meningkatkan
insidens kanker pada manusia atau hewan
– Penyebab sebagian besar kanker : unknown
– Multifaktorial
– Karsinogen yang sudah dikenal hanya sedikit
– Agen “lingkungan” yang belum teridentifikasi
sebagai karsinogen : berperan dalam 95% kejadian
kanker
Karsinogen
Chemicals
Biologic : Viruses, bacteria
Physics : Radiation
Hereditary causes- Genetic
defects.
Combination – common.
Klasifikasi karsinogen
Genotoxic
– bekerja langsung pada DNA atau pada ekspresi
DNA saat proses translasi
• DNA replication errors.
• Point mutations.
• Chromosomal aberration.
Epigenetic
– Non-DNA reactive.
– Potentiators.
– Ex.: hormone, immune function modifiers
GENOTOXIC CARCINOGEN
Chemical capable of producing cancer by directly altering the
genetic material of target cells.
1- Direct carcinogens (no metabolic activation).
– Alkylating agents.
2-Indirect carcinogens (metabolic activation).
– Polycyclic aromatic hydrocarbons.
– Aromatic amines.
– Nitrosamines.
– Natural substances.
3– Inorganic carcinogens.
4- Ni, Cr, Cd, As.
Epigenetic Carcinogen
Cytotoxic carcinogens.
– Nitrillotriacetate, BHA, BHT.
• Tumor promotors.
– DDT, Dioxin
• Hormones.
– Estradiol, DES
• Immunosuppressants.
– Cyclosporin A
• Particulates.
– Asbestos.
Agents
Causing Neoplasia
Chemical Oncogenesis
Radiation Oncogenesis
Viral Oncogenesis
Nutritional Oncogenesis
Hormonal Oncogenesis
Genetic Oncogenesis
1 - Chemical Carcinogenesis
• Chemical carcinogens adalah electrophiles atau dapat
dimetabolisme menjadi electrophiles (melalui aktivasi
metabolik). Electrophiles ini dapat bereaksi dengan
nucleophilic centers (predominantly N and O and to some
extent S) dalam makromolekul selular seperti DNA, RNA dan
protein.
• Jenis
• Proximate or direct-acting : act locally without
metabolic change
• Indirect acting : carcinogenic only after being
metabolised into active compounds (procarcinogen 
ultimate carcinogen)
Industrial Exposures

Benzidine
Urinary Bladder

Vinyl Chloride
Liver Mesenchyme

Certain tars
Asbestos
cigarette smoking)


Skin and
Peritoneum (lungs when combined with
Benzene
Lymphoid Tissue
Other Exposures




Diethylstilbestrol
Arsenic Compounds
Cigarette Smoke
Betal Nut
VaginaI
Skin cancer
Lungs, urinary tract
Buccal Mucosa
1 - Chemical Carcinogenesis
– 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
2 – Radiation Oncogenesis
– Jenis
• Ultraviolet
• X-ray
• Radioisotopes
• Nuclear Fallout
– Mode of oncogenesis
• Direct effect on DNA
• Activation of cellular oncogenes
2 – Radiation Oncogenesis
• Radiasi ionisasi : 2 mekanisme
– Ionisasi langsung – merusak DNA dan molekul lainnya,
mutasi somatik
– Efektor sekunder seperti radikal bebas yang terbentuk.
Radikal bebas akan merusak, membunuh sel dan
menginduksi mutasi
• X Ray workers – Leukemia
• Radio-isotopes – Thyroid carcinoma
• Atomic explosion – Skin cancer, Leukemia
2 – Radiation Oncogenesis
– Radiasi UV
• Nonionisasi
• skin cancers – squamous CA, basal cell CA, malignant
melanoma
• Kulit terang dan orang tua
• Sinar UV menginduksi cross-linkages antara molekul
DNA dan karsinogenesis terjadi bila mekanisme repair
tidak efisien
2 – Radiation Oncogenesis
– 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
2 – Radiation Oncogenesis
– Radioisotopes
• Osteosarcoma banyak diantara pekerja pabrik yang menggunakan
cat mengandung radium
• Pertambangan mineral radioaktif di Eropa dan Asia berkaitan
dengan kanker paru
• Thorium meningkatkan risiko kanker hepar– hepatocellular,
angiosarcoma, cholangiocarcinoma
• Radioactive iodine – meningkatkan risiko kanker 15-25 tahun
kemudian
– Nuclear Fallout
• Hiroshima, Nagasaki (atomic blasts)
• Marshall islands (atmospheric testing of nuclear divide containing
radioactive iodine)
• Chernobyl, 1986
3 – Viral Oncogenesis
– Jenis
• Oncogenic RNA Viruses
• Oncogenic DNA Viruses
– Mode of Oncogenesis
• RNA Virus
• DNA Virus
• Human Papilloma Virus
– Cervical neoplasia – warts, papilloma, ca cx
• Epstein-Barr virus –
– Burkitts Lymphoma, KNF.
• Hepatitis B & C virus
– Hepatocellular carcinoma.
3 – Viral Oncogenesis
• Virus berperan dalam patogenesis keganasan dengan mengintegrasikan
elemen genetik virus kedalam DNA inang.
• Gen baru ini diekspresikan oleh sel inang; pertumbuhan sel atau
pembelahan sel atau merusak gen normal yang berfungsi mengontrol
pertumbuhan dan pembelahan sel.
• Infeksi virus juga menyebabkan disfungsi imun, sehingga terjadi
penurunan immune surveillance untuk tumor yang baru terbentuk
• Insersi asam nukleat virus  mutasi
• Perubahan onkogen, gen supresor tumor dan gen DNA repair
mengakibatkan “up-regulation“ pembelahan sel  Carcinogenesis.
3 – Viral Oncogenesis
– Deteksi viral genome
• Identifikasi sekuens asam nukleat spesifik virus
dengan hibridisasi probe DNA/RNA
• Pengenalan antigen spesifik virus dalam sel
yang terinfeksi
• Deteksi virus-specific mRNA
4 – Nutritional Oncogenesis
– Hubungan kanker dengan diet
– Contoh
• Low-fiber diet dan KKR
• Fatty diet dan kanker payudara
• Daun sirih dan oral cancer
– Agen protektif– ?efek antioksidan ----- perlu konfirmasi
• Beta-carotene
• Vitamin C, E
• Selenium
5 – Hormonal Oncogenesis
– Types
• Induction of Neoplasms by Hormones
• Dependence of Neoplasms on Hormones
– Hormones inducing Neoplasms
• Estrogen – breast cancer
• Diethylstilbestrol (DES) – vaginal and uterine cancer
5 – Hormonal Oncogenesis
– Neoplasma yang tergantung faktor hormonal
• Neoplasma yang tidak disebabkan oleh hormon tetapi
tergantung pada hormon untuk dapat tumbuh optimal
• Sel neoplastik mempunyai reseptor hormon
• Hilangnya stimulasi hormon memperlambat tetapi tidak
menghentikan pertumbuhan
• Contoh
– Kanker prostat
– Kanker payudara
– Kanker tiroid
6 - Genetic Oncogenesis (Role of Inheritance)
– Types
• Mendelian inheritance
• Polygenic inheritance
• Association with inherited diseases
– Mendelian Inheritance
• Dominant
• Recessive
• Examples
– Retinoblastoma
– Wilm’s tumor
– Others
» Neurofibromatosis (type 1 von Recklinghausen’s disease)
» Multiple endocrine adenomatosis (MEN)
» Familial polyposis coli
» Nevoid basal cell carcinoma syndrome
6 - Genetic Oncogenesis (Role of Inheritance)
– Polygenic Inheritance
• Neoplasms occuring in related individuals more often than
expected on the basis of chance
– Breast CA
– Colon CA
– Association with Inherited Diseases
• Many inherited diseases are associated with higher risk of
neoplasia
• Types :
– Syndromes characterised by increased chromosomal fragility
– Syndromes of immunodeficiency
Hypotheses of the Origin of Neoplasia
• Multiple Hits and Multiple Factors
– Knudson : carcinogenesis memerlukan 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
Karsinogenesis
• Inisiasi
– Kerusakan DNA eg.Benzpyrene
• Promosi
– Perubahan histologik– eg. Turpentine (co-carcinogens)
• Malignant transformation/Progresi :
– Pembentukan tumor yang visible – kerusakan DNA
berlanjut
Initiation - point at which an irreversible alteration,
usually genetic, is introduced into a target cell.
(genotoxicity)=Interaction with DNA
Konversi proto-oncogen menjadi oncogen
Inisiasi:
(1) irreversible
(2) carcinogenic compounds
(3) Segera setelah paparan karsinogen
(4) Inisiasi saja tidak menyebabkan terbentuknya
tumor
Beberapa paparan terhadap inisiator dapat
menyebabkan terbentuknya tumor tanpa adanya
promoter.
Promotion is the process whereby an initiated tissue or
organ develop focal proliferations and it requires the
presence of continuous stimulation.
A promotor: is a substance which doesn't damage DNA
but enhance growth of tumor induced by genotoxic
carcinogens e.g.: skin cancer in mice can be induced by
application of benzo [α ] pyrene ( initiator) followed by
phorbol ester from cotton oil ( promoter).
Promotion
(1) reversible
(2) acts only after exposure to an initiating agent
(3) requires repeated administration of a
promoter
(4) is not carcinogenic in itself


Perubahan menetap gen dalam sel
yang terinisiasi
Mutasi lain atau faktor epigenetik
dapat mengubah fenotipe
keganasan, invasi dan metastasis
Etiology and Pathogenesis of Neoplasia
Initiation and Promotion
 Perubahan
ekspresi gen pada tingkat
transkripsi, translasi atau posttranslasi
 Penyebab







Metilasi DNA
Histone deacetylation
Perubahan stabilitas mRNA
Fosforilasi protein
Trafficking
Protein binding/complexing
Cell-cell communication