Carcinogenesis, Carcinogenic Agents and Their Cellular Interaction

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Carcinogenesis
A large number of agents cause genetic damage and induce neoplastic transformation of cells Chemical Carcinogens Radiant energy Oncogenic viruses and some other microbes

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Chemical Carcinogenesis
Experimental model:
INITIATION

Normal Cells

PROMOTION Cancer Cells

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Chemical Carcinogenesis is a Multistep Process

Stages of Chemical Carcinogenesis Initiation, likely represents a mutation in a single cell Promotion, follows initiation and reflects the clonal expansion of the initiated cells, and maintain it Progression, is the stage in which growth become autonomous, by this time, sufficient mutations have accumulated to immortalize cells Cancer, the end result of the entire sequence

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Initiation-promotion scheme

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INITIATION
Initiator 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 Carcinogen

Direct-acting Carcinogens Alkylating Agents Acylating agents Procarcinogen that Require Metabolic activation Polycyclic & Heterocyclic Aromatic Hydrocarbons Aromatic Amines, Amides, Azo Dyes Natural Plant and Microbial Products Others

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Chemical Carcinogens are Mostly Mutagen

A mutagen is an agent that can permanently alter the genetic constitution of a cell A mutagen is not necesserily a carcinogen Cell 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 Carcinogenesis
1. Direct acting compound do not require chemical transformation for their carcinogenicity 2. Indirect acting compound / procarcinogen, require metabolic conversion in vivo to produce ultimate carcinogen Property 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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Promoters
Promoters: phorbol esters, hormone, phenols, drugs Not 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 phophorylates several substrates involved in signal transduction pathways
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Tumor Promotion
Application of promoter leads to proliferation and clonal expansion of initiated (mutated) cells Initiated cells respond differently to promoters than do normal cells and hence expand selectively Tumor promotion includes multiple steps:

- Proliferation of preneoplastic cells - Malignant conversion - Tumor progression

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Aflatoxin Carcinogenesis

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Metal Carcinogen
Metals/metal compounds can induce cancer, but the mechanism is unkown Divalent metal cations (Ni++, Pb++, Cd++, Co++, Be++) are electrophilic possible to react with macromolecules Metal ions react with guanin and phosphate group of DNA Metal ions can depolymerize polynucleotides Bind to purine and pyrimidine bases through covalent binding Most metal-induced cancers occur in an occupational setting How do they occur in vivo is not known

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Radiation Carcinogenesis
Transform all kind of cells in vitro and induce neoplasms in vivo, in human & experimental animal UV light skin cancer Ionizing radiation of medical, occupational, and bomb of origins produce a variety of malignant neoplasms The effect of UV light is somewhat differ from those of ionizing radiation

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UV
UV effects on cells inhibition of cell division, inactivation of enzymes, induction of mutation, and killing the cells UV type: - UVA (320 400 nm): non-mutagenic - UVB (280 320 nm): mutagen, not filtered by ozone - UVC (200 280 nm): mutagen, filtered by ozone Type of cancer results are skin cancers: SCC, BCC, melanoma UVB 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 DNA

This 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 lesion 3. Removal of the damage nucleotide 4. Synthesis of a nucleotide patch 5. Synthesis of its ligation

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The Formation of Pyrimidine Dimers of the DNA

May 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 dimer Unless 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 genes Postulation: excessive sun exposure capacity of NER pathway in overwhelmed some DNA damage remains unrepaired large transcription errors cancer Xeroderma pigmentosum (photosensitivity, 200fold risk of ckin cancer) has several mutated genes involved in NER
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Ionizing Radiation
Electromagnetic radiation - X-rays and gamma rays Particulate radiation - particles, particles, proton, neutron

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Hierarchy of Vulnerability

1. Leukemia 2. Thyroid 3. Breast, lung, salivary gland (intermediate) 4. Skin, bone, gastrointestinal tract (relatively resistant)

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Viral & Microbial Oncogenesis

Virus: DNA & RNA (retrovirus/oncorna virus), some carry oncogene, some dont Microbial Helicobacter pylori

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Virus DNA
A Cytopathic Virus The virus is integrated into the host genom cell transformation The integrated genes by the virus which produce cell transformation expressed inside transformed cells The 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 Ca Low risk: the dominant are 6 & 11 genital wart with low malignant potential Strain 1, 2, 4, 7 papilloma Oncoprotein 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 NPC EBV infects oropharynx epithelial and the B cell (via receptor CD21) cell immortalization Oncoprotein: LMP-1 inhibit apoptosis by upregulating bcl-2, and activates growth-promoting pathways EBNA-2: transactivation several host genes (cyclin D and src family members), and activate transcription of LMP-1
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Virus DNA onkogenik

EBV

Translocation of MYC (mutation)

Limfoma Burkitt

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HBV(Hepatitis B Virus)
HBV infection increases the risk of the development of HCC 200X The 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 hyperplasia 2. HBV codes the protein HBx destroy normal development control 3. HBx binding to p53 inactivated suppresion
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KSHV

(Kaposi Sarcoma Herpes Virus)

Ther member of herpes virus family Etiological factor etiology for Kaposi sarcoma especially in the imunodefficient individuals (AIDS) The basic pathogenesis is multifactorial: 1. Severe T cell imunity defect 2. Disregulation of B cell and monocyte 3. Multiple known viral infection (HHV type 8, EBV, HPV), and unknown virus
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Retrovirus: HTLV-1
Human 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, breastfeeding Leukemia: only 1% of all infected person after latent period of 20-30 years

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Retrovirus

HTLV-1
Is a lymphotrophic agent

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Helicobacter pylori
Infection Only 20-30% : ulcers Strong relationship

Epidemiologic study:
- Detection of HP infection in the

great majority of gastric lymphoma

Carcinoma

- Treatment of HP infection with antibiotics results in regression of the

lymphoma in most cases

Lymphoma
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Helicobacter pylori
The strain causing disease contain pathogenic island containing CagA (cytotoxin associated gene A) and secretory system injects the CagA protein into the host cells Gene 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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(mucosal associated lymphoid tissue / MALT MALTOMA)

Gastric Lymphoma

-The B-cell that give rise to this tumor normally reside in the marginal zone marginal zone lymphoma -Infection lymphoid infiltrates B-cells actively proliferate may acquire genetic abnormalities such as 11;18 translocation

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