BLOK 2.

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 Vinyl Chloride Certain tars

Urinary Bladder Liver Mesenchyme Skin and Peritoneum (lungs when combined with Lymphoid Tissue

Asbestos cigarette smoking)

Benzene

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 Wilms tumor Others Neurofibromatosis (type 1 von Recklinghausens 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 [ ] 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