cancer

KARSINOGENESIS

KARSINOGENESIS
dr 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 selKanker terjadi karena mutasi somatikGenetic change : mutasi DNAEpigenetic change : perubahan ekspresi gen tanpa perubahan DNAMutasi tunggal belum cukup untuk menyebabkan kankerKanker berkembang dari aberasi ringan selInsidens 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 kimiawiBahan 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 genesLoss/damage to Apoptosis genesLoss/damage of DNA repair genes.

Istilah
Carcinogenesis: Pathogenesis of cancerCarcinogen - agent causing cancer.Oncogen - agent causing neoplasm.Mutagen - agent causing mutation.Oncogenes genes causing cancerp-onc, v-onc Proto/viral/ - naming of oncogenes.

Karsinogen bahan yang sudah diketahui menyebabkan kanker atau meningkatkan insidens kanker pada manusia atau hewanPenyebab sebagian besar kanker : unknownMultifaktorialKarsinogen yang sudah dikenal hanya sedikitAgen 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 Carcinogen
Cytotoxic 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.JenisProximate or direct-acting : act locally without metabolic changeIndirect 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 ExposuresDiethylstilbestrol VaginaI Arsenic Compounds Skin cancerCigarette Smoke Lungs, urinary tract Betal Nut Buccal Mucosa

1 - Chemical Carcinogenesis
Mode of carcinogenesisInducing changes in DNA eg. Base alkylation, deletion, breakage, cross-linkageEpigenetic mechanismsSynergistic action with virusesPromoter for other carcinogensDifficulties in identifying carcinogenNumerous industrial, agricultural, household chemicals present in low levelsExposed to large number of chemicals in a lifetimeLong lag phase

2 Radiation Oncogenesis
JenisUltravioletX-rayRadioisotopesNuclear FalloutMode of oncogenesisDirect effect on DNAActivation of cellular oncogenes

Radiasi ionisasi : 2 mekanismeIonisasi langsung merusak DNA dan molekul lainnya, mutasi somatikEfektor sekunder seperti radikal bebas yang terbentuk. Radikal bebas akan merusak, membunuh sel dan menginduksi mutasi

X Ray workers LeukemiaRadio-isotopes Thyroid carcinomaAtomic explosion Skin cancer, Leukemia

Radiasi UVNonionisasiskin cancers squamous CA, basal cell CA, malignant melanomaKulit terang dan orang tuaSinar UV menginduksi cross-linkages antara molekul DNA dan karsinogenesis terjadi bila mekanisme repair tidak efisien

X-ray radiationEarlier use of X-rays caused skin cancer, leukemia and papillary thyroid CARadiotherapy causes raditation-induced malignancy 10-30 yrs later usually sarcomasDiagnostic X-rays are considered to have no increased risk except in abdominal x-rays which increase incidence of leukemia in the fetus

RadioisotopesOsteosarcoma banyak diantara pekerja pabrik yang menggunakan cat mengandung radiumPertambangan mineral radioaktif di Eropa dan Asia berkaitan dengan kanker paruThorium meningkatkan risiko kanker hepar hepatocellular, angiosarcoma, cholangiocarcinomaRadioactive iodine meningkatkan risiko kanker 15-25 tahun kemudianNuclear FalloutHiroshima, Nagasaki (atomic blasts)Marshall islands (atmospheric testing of nuclear divide containing radioactive iodine)Chernobyl, 1986

3 Viral Oncogenesis
Jenis Oncogenic RNA VirusesOncogenic DNA VirusesMode of OncogenesisRNA Virus DNA VirusHuman Papilloma Virus Cervical neoplasia warts, papilloma, ca cxEpstein-Barr virus Burkitts Lymphoma, KNF.Hepatitis B & C virusHepatocellular 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 terbentukInsersi asam nukleat virus mutasiPerubahan onkogen, gen supresor tumor dan gen DNA repair mengakibatkan up-regulation pembelahan sel Carcinogenesis.

3 Viral Oncogenesis
Deteksi viral genomeIdentifikasi sekuens asam nukleat spesifik virus dengan hibridisasi probe DNA/RNAPengenalan antigen spesifik virus dalam sel yang terinfeksiDeteksi virus-specific mRNA

4 Nutritional Oncogenesis
Hubungan kanker dengan dietContohLow-fiber diet dan KKRFatty diet dan kanker payudaraDaun sirih dan oral cancer

Agen protektif ?efek antioksidan ----- perlu konfirmasiBeta-caroteneVitamin C, ESelenium

5 Hormonal Oncogenesis
TypesInduction of Neoplasms by HormonesDependence of Neoplasms on HormonesHormones inducing NeoplasmsEstrogen breast cancerDiethylstilbestrol (DES) vaginal and uterine cancer

5 Hormonal Oncogenesis
Neoplasma yang tergantung faktor hormonalNeoplasma yang tidak disebabkan oleh hormon tetapi tergantung pada hormon untuk dapat tumbuh optimalSel neoplastik mempunyai reseptor hormonHilangnya stimulasi hormon memperlambat tetapi tidak menghentikan pertumbuhanContohKanker prostatKanker payudaraKanker tiroid

6 - Genetic Oncogenesis (Role of Inheritance)
TypesMendelian inheritancePolygenic inheritanceAssociation with inherited diseasesMendelian InheritanceDominantRecessiveExamplesRetinoblastoma Wilms tumor OthersNeurofibromatosis (type 1 von Recklinghausens disease)Multiple endocrine adenomatosis (MEN)Familial polyposis coliNevoid basal cell carcinoma syndrome

6 - Genetic Oncogenesis (Role of Inheritance)
Polygenic InheritanceNeoplasms occuring in related individuals more often than expected on the basis of chanceBreast CA Colon CAAssociation with Inherited DiseasesMany inherited diseases are associated with higher risk of neoplasiaTypes :Syndromes characterised by increased chromosomal fragilitySyndromes of immunodeficiency

Hypotheses of the Origin of Neoplasia
Multiple Hits and Multiple FactorsKnudson : carcinogenesis memerlukan 2 hits1st event initiationCarcinogen = initiator2nd event promotionAgent = promoterMultiple hits occur 5 or moreEach hit produces a change in the genome which is transmitted to its progeny (ie. clone)Lag periodTime between exposure (first hit) and development of clinically apparent cancerAltered cell shows no abnormality during lag period

Karsinogenesis
Inisiasi Kerusakan DNA eg.BenzpyrenePromosi 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 apromoter(4) is not carcinogenic in itself

Perubahan menetap gen dalam sel yang terinisiasiMutasi 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 posttranslasiPenyebabMetilasi DNAHistone deacetylationPerubahan stabilitas mRNAFosforilasi proteinTraffickingProtein binding/complexingCell-cell communication

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Major chemical carcinogensPolycyclic hydrocarbonsAromatic aminesAflatoxinsNitrosaminesCancer chemotherapeutic agentsAsbestosHeavy metalsVinyl chloride

See table on major chemical carcinogens and their cancers
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PotencyVaries with carcinogenExpressed in amount that must be given to induce cancer on a regular basis (Eg. Saccharin 10g/kg/d, aflatoxin 10-6 g/kg/d)
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X-rays, radioisotopes and nuclear power plants account for

cancer

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