Carcinogenic Agents and Their Cellular Interaction

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CarcinogenesisA large number of agents cause genetic damage and induce neoplastic transformation of cellsChemical CarcinogensRadiant energyOncogenic viruses and some other microbes

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Chemical CarcinogenesisExperimental model: Normal Cells

INITIATION

PROMOTION

Cancer Cells

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Chemical Carcinogenesis is a Multistep ProcessStages of Chemical CarcinogenesisInitiation, likely represents a mutation in a single cellPromotion, follows initiation and reflects the clonal expansion of the initiated cells, and maintain itProgression, is the stage in which growth become autonomous, by this time, sufficient mutations have accumulated to immortalize cellsCancer, the end result of the entire sequence

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Initiation-promotion scheme

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INITIATIONInitiator alone is not sufficient for tumor formation (Group 1)Initiation results from exposure of cells to an appropriate dose of initiator (carcinogenic agents)Initiation irreversible mutation (DNA damage) memory months later +promoter tumor (Group 2&3)

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PROMOTION

promoter is non-tumorigenic by itself Induce tumors in initiated cells (Group 5) When promoter is applied before initiator, no tumor developed (Group 4) When the time between multiple application is extended the effect of promoter is reversible tumors failed to develop (Group 6)

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Initiation&Promotion

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Initiation & promotion

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Events in Chemical Carcinogenesis

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Major Chemical CarcinogenDirect-acting CarcinogensAlkylating AgentsAcylating agentsProcarcinogen that Require Metabolic activationPolycyclic & Heterocyclic Aromatic HydrocarbonsAromatic Amines, Amides, Azo DyesNatural Plant and Microbial ProductsOthers

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Chemical Carcinogens are Mostly MutagenA mutagen is an agent that can permanently alter the genetic constitution of a cellA mutagen is not necesserily a carcinogenCell culture good method to study:- mutation, assays of mutagenicity- unscheduled DNA synthesis- DNA strand breaks- Screening for carcinogenic potential of chemicals

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Initiation of Carcinogenesis1. Direct acting compound do not require chemical transformation for their carcinogenicity2. Indirect acting compound / procarcinogen, require metabolic conversion in vivo to produce ultimate carcinogenProperty in common:= They are highly reactive electrophiles that can react with nucleophilic sites in the cell electrophilic reaction sub-lethal damage to DNA= Molecular fingerprint

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Carcinogen tumor types (fingerprinting)

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PromotersPromoters: phorbol esters, hormone, phenols, drugsNot mutagenic how do they contribute to tumorigenesis study of TPA (tetradecanoyl phorbol-13 acetate)TPA: - phorbol esters - powerful activator for protein kinase C, an enzyme that phophrylates several substrates involved in signal transduction pathways

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Tumor PromotionApplication of promoter leads to proliferation and clonal expansion of initiated (mutated) cellsInitiated cells respond differently to promoters than do normal cells and hence expand selectivelyTumor promotion includes multiple steps:- Proliferation of preneoplastic cells- Malignant conversion- Tumor progression

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Aflatoxin Carcinogenesis

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Metal CarcinogenMetals/metal compounds can induce cancer, but the mechanism is unkownDivalent metal cations (Ni++, Pb++, Cd++, Co++, Be++) are electrophilic possible to react with macromoleculesMetal ions react with guanin and phosphate group of DNAMetal ions can depolymerize polynucleotides Bind to purine and pyrimidine bases through covalent bindingMost metal-induced cancers occur in an occupational settingHow do they occur in vivo is not known

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Kanker - Pekerjaan

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Radiation CarcinogenesisTransform all kind of cells in vitro and induce neoplasms in vivo, in human & experimental animalUV light skin cancerIonizing radiation of medical, occupational, and bomb of origins produce a variety of malignant neoplasmsThe effect of UV light is somewhat differ from those of ionizing radiation

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UVUV effects on cells inhibition of cell division, inactivation of enzymes, induction of mutation, and killing the cellsUV type:- UVA (320 400 nm): non-mutagenic- UVB (280 320 nm): mutagen, not filtered by ozone- UVC (200 280 nm): mutagen, filtered by ozoneType of cancer results are skin cancers: SCC, BCC, melanomaUVB also causes mutation in oncogenes (ras) and tumor suppressor genes (p53)

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The carcinogenicity of UVB is attributed to its formation of pyrimidine dimers in DNAThis DNA damage is repaired by NER (nucleotide excision repair)1. Recognition of the DNA lesion 2. Incision of the damage strand on both sites of the lesion3. Removal of the damage nucleotide4. Synthesis of a nucleotide patch5. Synthesis of its ligation

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The Formation of Pyrimidine Dimers of the DNAMay between thymine & thymine, thymine & cytosine, cytosine pairs alone leads to cyclobutane ring distort the phosphodiester backbone of the double helix in the region of each dimerUnless repaired by NER genomic mutation produced by UV radiation is mutagenic and carcinogenic

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NER (nucleotide excision repair)This process needs at least the product of 20 genesPostulation: excessive sun exposure capacity of NER pathway in overwhelmed some DNA damage remains unrepaired large transcription errors cancerXeroderma pigmentosum (photosensitivity, 200-fold risk of ckin cancer) has several mutated genes involved in NER

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Ionizing RadiationElectromagnetic radiation- X-rays and gamma raysParticulate radiation- particles, particles, proton, neutron

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Hierarchy of VulnerabilityLeukemiaThyroidBreast, lung, salivary gland (intermediate)Skin, bone, gastrointestinal tract (relatively resistant)

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Viral & Microbial OncogenesisVirus: DNA & RNA (retrovirus/oncorna virus), some carry oncogene, some dontMicrobial Helicobacter pylori

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Virus DNAA Cytopathic VirusThe virus is integrated into the host genom cell transformationThe integrated genes by the virus which produce cell transformation expressed inside transformed cellsThe important viruses: HPV, EBV, HBV, KSHV

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HPV (Human Papilloma Virus)High risk: strain 16, 18, and the less found are strain 31, 33, 35, dan 51 invasive SCC (85%) with the tumor precursors: severe dysplasia and in situ CaLow risk: the dominant are 6 & 11 genital wart with low malignant potentialStrain 1, 2, 4, 7 papillomaOncoprotein from type 16 & 18 can interact (binding) with p53 and pRb with high affinity cell transformation

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Effect of HPV Protein E6 & E7 on the Cell Cycle

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EBV(Epstein Barr virus)Has role in the pathogenesis tumor: lymphoma Burkitt (African form), B cell lymphoma in person with immunosuppression, Hodgkin lymphoma, and NPCEBV infects oropharynx epithelial and the B cell (via receptor CD21) cell immortalizationOnkoprotein: LMP-1 inhibit apoptosis by up-regulating bcl-2, and activates growth-promoting pathwaysEBNA-2: transactivation several host genes (cyclin D and src family members), and activate transcription of LMP-1

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Virus DNA onkogenikEBVTranslocation of MYC(mutation) Limfoma Burkitt

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HBV(Hepatitis B Virus)HBV infection increases the risk of the development of HCC 200XThe virus is integrated into the liver cell genom, but not developing oncoprotein no consistent pattern of oncogenesis maybe the effects are indirect:1. Chronic inflammation cirrhosis regenerative hyperplasia2. HBV codes the protein HBx destroy normal development control3. HBx binding to p53 inactivated suppresion

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KSHV (Kaposi Sarcoma Herpes Virus)Ther member of herpes virus familyEtiological factor etiology for Kaposi sarcoma especially in the imunodefficient individuals (AIDS)The basic pathogenesis is multifactorial:1. Severe T cell imunity defect2. Disregulation of B cell and monocyte3. Multiple known viral infection (HHV type 8, EBV, HPV), and unknown virus

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Retrovirus: HTLV-1Human T-cell Leukemia Virus Type 1 the one that recognized oncogenic to human (a lot in animal)The tendency of infection to limfocyte CD4+Sexual intercourse infection, blood, breast-feedingLeukemia: only 1% of all infected person after latent period of 20-30 years

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RetrovirusHTLV-1Is a lymphotropic agent

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Helicobacter pyloriCarcinoma Lymphoma Strong relationship

Epidemiologic study: Detection of HP infection in the great majority of gastric lymphoma Treatment of HP infection with anti- biotics results in regression of the lymphoma in most casesInfection Only 20-30% : ulcers

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Helicobacter pyloriThe strain causing disease contain pathogenic island containing CagA (cytotoxin associated gene A) and secretory system injects the CagA protein into the host cellsGene associated with virulence: VacA (encode vacuolated toxin that causes apoptosis)The infection is associated with adenocarcinomas of the intestinal type (sequence: chronic gastritis multifocal atrophy with lower gastric acid secretion intestinal metaplasia dysplasia carcinoma)

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Gastric Lymphoma(mucosal associated lymphoid tissue / MALT MALTOMA)The B-cell that give rise to this tumor normally reside in the marginal zone marginal zone lymphomaInfection lymphoid infiltrates B-cells actively proliferate may acquire genetic abnormalities such as 11;18 translocation

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