Karsinogenesis
Karsinogenesis
KARSINOGENESIS
dr ASWIYANTI ASRI,M.Si.Med,SpPA
Karsinogenesis
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
Other Exposures
Diethylstilbestrol VaginaI
Arsenic Compounds Skin cancer
Cigarette Smoke Lungs, urinary tract
Betal Nut 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
– 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
– 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
Inisiasi:
(1) irreversible
(2) carcinogenic compounds
(3) Segera setelah paparan karsinogen
(4) Inisiasi saja tidak menyebabkan terbentuknya
tumor
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