karsinogenesis - akper al-ikhlas...
TRANSCRIPT
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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
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
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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
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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
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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.
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.
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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
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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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