BLOK 2.1 KARSINOGENESIS. dr ASWIYANTI ASRI,M.Si.Med,SpPA

(1)

KARSINOGENESIS

dr ASWIYANTI ASRI,M.Si.Med,SpPA

(2)

Karsinogenesis

the process by which a

normal cell is transformed

into a malignant cell and

repeatedly divides to become

a cancer.

(3)

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

(4)

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.

(5)

Non-lethal Genetic damage

lies at the center of

carcinogenesis.

• _{Loss/damage to suppressor genes,}

• _{Duplication of promotor genes}

• _{Loss/damage to Apoptosis genes}

(6)

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.

(7)

• 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

(8)

Karsinogen



Chemicals



Biologic : Viruses, bacteria



Physics : Radiation

Hereditary causes- Genetic

defects.

(9)

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.

(10)

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.

(11)

Epigenetic Carcinogen

Cytotoxic carcinogens.

– Nitrillotriacetate, BHA, BHT.

• Tumor promotors.

– DDT, Dioxin

• Hormones.

– Estradiol, DES

• Immunosuppressants.

– Cyclosporin A

• Particulates.

– Asbestos.

(12)



Agents Causing Neoplasia



Chemical Oncogenesis



Radiation Oncogenesis



Viral Oncogenesis



Nutritional Oncogenesis



Hormonal Oncogenesis



Genetic Oncogenesis

(13)

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)

(14)

(15)

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

(16)

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

(17)

2 – Radiation Oncogenesis

– Jenis

• Ultraviolet

• X-ray

• Radioisotopes

• Nuclear Fallout

– Mode of oncogenesis

• Direct effect on DNA

(18)

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

(19)

(20)

(21)

(22)

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

(23)

(24)

(25)

(26)

(27)

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

(28)

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)

(29)

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

(30)

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

(31)

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

(32)

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

(33)

(34)

(35)

(36)

(37)

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

(38)

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

(39)

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

(40)

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

(41)

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

(42)

(43)

Karsinogenesis

• Inisiasi

– Kerusakan DNA eg.Benzpyrene

• Promosi

– Perubahan histologik– eg. Turpentine (co-carcinogens)

• Malignant transformation/Progresi :

– Pembentukan tumor yang visible – kerusakan DNA berlanjut

(44)

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.

(45)

(46)

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

(47)

(48)



Perubahan menetap gen dalam

sel yang terinisiasi



Mutasi lain atau faktor

epigenetik dapat mengubah

fenotipe keganasan, invasi dan

metastasis

(49)

(50)

(51)

Etiology and Pathogenesis of Neoplasia Initiation and Promotion

(52)

(53)

(54)



Perubahan ekspresi gen pada tingkat

transkripsi, translasi atau posttranslasi



Penyebab

Metilasi DNA

Histone deacetylation

Perubahan stabilitas mRNA

Fosforilasi protein

Trafficking

Protein binding/complexing

(55)

(56)

(57)

(58)

(59)