KARSINOGENESISdr ASWIYANTI ASRI,M.Si.Med,SpPA

BLOK 2.1

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

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 CarcinogenEpigenetic CarcinogenCytotoxic carcinogens.– Nitrillotriacetate, BHA, BHT.• Tumor promotors.– DDT, Dioxin• Hormones.– Estradiol, DES• Immunosuppressants.– Cyclosporin A• Particulates.– Asbestos.

Agents Causing NeoplasiaChemical OncogenesisRadiation OncogenesisViral OncogenesisNutritional OncogenesisHormonal OncogenesisGenetic 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 Skin and Asbestos Peritoneum (lungs when

combined with cigarette smoking) Benzene Lymphoid Tissue

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

• 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 apromoter(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 NeoplasiaInitiation and Promotion

Perubahan ekspresi gen pada tingkat transkripsi, translasi atau posttranslasi

PenyebabMetilasi DNAHistone deacetylationPerubahan stabilitas mRNAFosforilasi proteinTraffickingProtein binding/complexingCell-cell communication