karsinogenesis - akper al-ikhlas...

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KARSINOGENESISMei Vita Cahya Ningsih

Karsinogenesis

the process by which a normal cell is

transformed into a malignant cell

and repeatedly divides to become a

cancer.

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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.

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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.

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• 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.

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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.

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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

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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)

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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

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2 – Radiation Oncogenesis

• Jenis

• Ultraviolet

• X-ray

• Radioisotopes

• Nuclear Fallout

• Mode of oncogenesis

• Direct effect on DNA

• Activation of cellular oncogenes


• 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

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• 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

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• 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


• 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

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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.


• 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.

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• 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

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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

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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

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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

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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.

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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

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� Perubahan menetap gen dalam sel yang terinisiasi

� Mutasi lain atau faktor epigenetik dapat mengubah fenotipe keganasan, invasi dan metastasis

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Etiology and Pathogenesis of Neoplasia

Initiation and Promotion

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� 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

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