dr ASWIYANTI ASRI,M.Si.Med,SpPA BLOK 2.1 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 Carcinogen 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) Major chemical carcinogens Polycyclic hydrocarbons Aromatic amines Aflatoxins Nitrosamines Cancer chemotherapeutic agents Asbestos Heavy metals Vinyl chloride See table on major chemical carcinogens and their cancers

Chemicals Carcinogenic in Humans 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 Potency Varies with carcinogen Expressed in amount that must be given to induce cancer on a regular basis (Eg. Saccharin – 10g/kg/d, aflatoxin – 10-6 g/kg/d)

2 – Radiation Oncogenesis Jenis Ultraviolet X-ray Radioisotopes Nuclear Fallout Mode of oncogenesis Direct effect on DNA Activation of cellular oncogenes X-rays, radioisotopes and nuclear power plants account for <1% of total radiation exposure. The remainder comes from background radiation – ie. radiaoctive rocks, earth core, cosmic rays

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 Radium is metabolised and incorporated into bone like calcium Thorium – used in diagnostic radiology (1930-1955)

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. RNA Virus Introduction of DNA provirus containing oncogene (v-onc) Insertion of DNA provirus adjacent to cellular oncogene (c-onc) DNA Virus Inactivation of tumor-suppressor gene proteins Enhancement of oncogene action

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 Estrogen Granulosa cell tumor and recurrent ovulatory failure result in increased risk of endometrial CA endometrial hyperplasia  dysplasia  neoplasia Minimal increase in risk of breast CA with high-dose estrogen OCP Diethylstilbestrol (DES) Female children exposed to DES in utero  high risk of vaginal clear-cell CA Steroid hormones OCP and anabolic steroids associated with liver cell adenoma, carcnoma

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 Dominant – gene codes for activation factor Recessive – absence of tumor suppresor genes lead to failure in production of tumor suppressing factor See table on tumor suppressor genes.

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 Breast CA – 1st degree female relatives of premenopausal women with breast CA have 5X higher risk. The risk is higher when the relative has bilateral breast CA. Colon CA – occurs in families both as a complication of inherited familial polyposis coli and independently. 1/4th colon cancer patients demonstrate abnormalities of MSH2 gene which encodes a DNA housekeeper protein

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 a promoter (4) is not carcinogenic in itself

Progresi Perubahan menetap gen dalam sel yang terinisiasi Mutasi lain atau faktor epigenetik dapat mengubah fenotipe keganasan, invasi dan metastasis

Increased growth and expansion of the clone of cancerous cells

Etiology and Pathogenesis of Neoplasia Initiation and Promotion

Epigenetic change 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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