Post on 04-Apr-2018
transcript
7/29/2019 carcinogenesis cqrcinogenic agents 2010
1/39
28/11/2005 tums-pafkugm 1
Carcinogenesis,
Carcinogenic Agentsand
Their Cellular Interaction
7/29/2019 carcinogenesis cqrcinogenic agents 2010
2/39
28/11/2005 tums-pafkugm 2
Carcinogenesis
A large number of agents cause geneticdamage and induce neoplastic
transformation of cells Chemical Carcinogens
Radiant energy
Oncogenic viruses and some othermicrobes
7/29/2019 carcinogenesis cqrcinogenic agents 2010
3/39
28/11/2005 tums-pafkugm 3
7/29/2019 carcinogenesis cqrcinogenic agents 2010
4/39
28/11/2005 tums-pafkugm 4
Experimental model: Normal Cells
INITIATION
PROMOTION
Cancer Cells
Chemical Carcinogenesis
7/29/2019 carcinogenesis cqrcinogenic agents 2010
5/39
28/11/2005 tums-pafkugm 5
Chemical Carcinogenesis is a
Multistep ProcessStages of Chemical Carcinogenesis
Initiation, likely represents a mutation in a single cell
Promotion, follows initiation and reflects the clonalexpansion of the initiated cells, and maintain it
Progression, is the stage in which growth becomeautonomous, by this time, sufficient mutations haveaccumulated to immortalize cells
Cancer, the end result of the entire sequence
7/29/2019 carcinogenesis cqrcinogenic agents 2010
6/39
28/11/2005 tums-pafkugm 6
Initiation-promotion scheme
7/29/2019 carcinogenesis cqrcinogenic agents 2010
7/39
28/11/2005 tums-pafkugm 7
INITIATION
Initiator alone is not sufficient for tumorformation (Group 1)
Initiation results from exposure of cells to an
appropriate dose of initiator (carcinogenicagents)
Initiation irreversible mutation (DNAdamage) memory months later
+promoter tumor (Group 2&3)
7/29/2019 carcinogenesis cqrcinogenic agents 2010
8/39
28/11/2005 tums-pafkugm 8
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)
7/29/2019 carcinogenesis cqrcinogenic agents 2010
9/39
28/11/2005 tums-pafkugm 9
Initiation
&
Promotion
7/29/2019 carcinogenesis cqrcinogenic agents 2010
10/39
28/11/2005 tums-pafkugm 10
Initiation&
promotion
7/29/2019 carcinogenesis cqrcinogenic agents 2010
11/39
28/11/2005 tums-pafkugm 11
Events in ChemicalCarcinogenesis
7/29/2019 carcinogenesis cqrcinogenic agents 2010
12/39
28/11/2005 tums-pafkugm 12
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
7/29/2019 carcinogenesis cqrcinogenic agents 2010
13/39
28/11/2005 tums-pafkugm 13
Chemical Carcinogens are MostlyMutagen
A mutagen is an agent that can permanently alter thegenetic 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
7/29/2019 carcinogenesis cqrcinogenic agents 2010
14/39
28/11/2005 tums-pafkugm 14
Initiation of Carcinogenesis
1. Direct acting compound do not require chemicaltransformation for their carcinogenicity
2. Indirect acting compound / procarcinogen, requiremetabolic conversion in vivo to produce ultimatecarcinogen
Property in common:
= They are highly reactive electrophiles that can reactwith nucleophilic sites in the cell electrophilic
reaction sub-lethal damage to DNA
= Molecularfingerprint
7/29/2019 carcinogenesis cqrcinogenic agents 2010
15/39
28/11/2005 tums-pafkugm 15
Carcinogen tumor types (fingerprinting)
7/29/2019 carcinogenesis cqrcinogenic agents 2010
16/39
28/11/2005 tums-pafkugm 16
Promoters
Promoters: phorbol esters, hormone, phenols,drugs
Not mutagenic how do they contribute totumorigenesis 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 transductionpathways
7/29/2019 carcinogenesis cqrcinogenic agents 2010
17/39
28/11/2005 tums-pafkugm 17
Tumor Promotion
Application of promoter leads to proliferation andclonal expansion of initiated (mutated) cells
Initiated cells respond differently to promoters thando normal cells and hence expand selectively
Tumor promotion includes multiple steps:
- Proliferation of preneoplastic cells
- Malignant conversion
- Tumor progression
7/29/2019 carcinogenesis cqrcinogenic agents 2010
18/39
28/11/2005 tums-pafkugm 18
AflatoxinCarcinogenesis
7/29/2019 carcinogenesis cqrcinogenic agents 2010
19/39
28/11/2005 tums-pafkugm 19
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 covalentbinding
Most metal-induced cancers occur in an occupationalsetting
How do they occur in vivo is not known
7/29/2019 carcinogenesis cqrcinogenic agents 2010
20/39
28/11/2005 tums-pafkugm 20
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 ofionizing radiation
7/29/2019 carcinogenesis cqrcinogenic agents 2010
21/39
28/11/2005 tums-pafkugm 21
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)
7/29/2019 carcinogenesis cqrcinogenic agents 2010
22/39
28/11/2005 tums-pafkugm 22
The carcinogenicity of UVB is attributed to itsformation 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 sitesof the
lesion
3. Removal of the damage nucleotide
4. Synthesis of a nucleotide patch5. Synthesis of its ligation
7/29/2019 carcinogenesis cqrcinogenic agents 2010
23/39
28/11/2005 tums-pafkugm 23
The Formation of
Pyrimidine Dimers of the DNA May between thymine & thymine, thymine &
cytosine, cytosine pairs alone leads to
cyclobutane ring distort the phosphodiesterbackbone of the double helix in the region of
each dimer
Unless repaired by NER genomic mutation
produced by UV radiation is mutagenic and
carcinogenic
7/29/2019 carcinogenesis cqrcinogenic agents 2010
24/39
28/11/2005 tums-pafkugm 24
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 DNAdamage remains unrepaired large
transcription errors cancer
Xeroderma pigmentosum (photosensitivity, 200-
fold risk of ckin cancer) has several mutated
genes involved in NER
7/29/2019 carcinogenesis cqrcinogenic agents 2010
25/39
28/11/2005 tums-pafkugm 25
Ionizing Radiation
Electromagnetic radiation
- X-rays and gamma rays
Particulate radiation
- particles, particles, proton,
neutron
7/29/2019 carcinogenesis cqrcinogenic agents 2010
26/39
28/11/2005 tums-pafkugm 26
Hierarchy of Vulnerability
1. Leukemia
2. Thyroid
3. Breast, lung, salivary gland(intermediate)
4. Skin, bone, gastrointestinal tract
(relatively resistant)
7/29/2019 carcinogenesis cqrcinogenic agents 2010
27/39
28/11/2005 tums-pafkugm 27
Viral & Microbial Oncogenesis
Virus: DNA & RNA (retrovirus/oncorna virus),some carry oncogene, some dont
Microbial Helicobacter pylori
7/29/2019 carcinogenesis cqrcinogenic agents 2010
28/39
28/11/2005 tums-pafkugm 28
Virus DNA
A Cytopathic Virus The virus is integrated into the host
genom cell transformation
The integrated genes by the virus whichproduce cell transformation expressed
inside transformed cells
The important viruses: HPV, EBV, HBV,KSHV
7/29/2019 carcinogenesis cqrcinogenic agents 2010
29/39
28/11/2005 tums-pafkugm 29
HPV (Human Papilloma Virus)
High risk: strain 16, 18, and the less found arestrain 31, 33, 35, dan 51 invasive SCC (85%)with the tumor precursors: severe dysplasia andin situ Ca
Low risk: the dominant are 6 & 11 genital wartwith low malignant potential
Strain 1, 2, 4, 7 papilloma
Oncoprotein from type 16 & 18 can interact
(binding) with p53 and pRb with high affinitycell transformation
7/29/2019 carcinogenesis cqrcinogenic agents 2010
30/39
28/11/2005 tums-pafkugm 30
Effect of HPV Protein E6 & E7 onthe Cell Cycle
7/29/2019 carcinogenesis cqrcinogenic agents 2010
31/39
28/11/2005 tums-pafkugm 31
EBV(Epstein Barr virus) Has role in the pathogenesis tumor: lymphoma
Burkitt (African form), B cell lymphoma in personwith immunosuppression, Hodgkin lymphoma,and NPC
EBV infects oropharynx epithelial and the B cell
(via receptor CD21) cell immortalization Oncoprotein: LMP-1 inhibit apoptosis by up-
regulating bcl-2, and activates growth-promotingpathways
EBNA-2: transactivation several host genes(cyclin D and srcfamily members), and activatetranscription of LMP-1
7/29/2019 carcinogenesis cqrcinogenic agents 2010
32/39
28/11/2005 tums-pafkugm 32
Virus DNA onkogenik
EBV
Translocation of MYC(mutation)
Limfoma Burkitt
7/29/2019 carcinogenesis cqrcinogenic agents 2010
33/39
28/11/2005 tums-pafkugm 33
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 normaldevelopment control
3. HBx binding to p53 inactivated suppresion
7/29/2019 carcinogenesis cqrcinogenic agents 2010
34/39
28/11/2005 tums-pafkugm 34
KSHV (Kaposi Sarcoma Herpes Virus)
Ther member of herpes virus family
Etiological factor etiology for Kaposi sarcomaespecially 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 type8, EBV, HPV), and unknown virus
7/29/2019 carcinogenesis cqrcinogenic agents 2010
35/39
28/11/2005 tums-pafkugm 35
Retrovirus: HTLV-1
Human T-cell Leukemia Virus Type 1
the onethat recognized oncogenic to human (a lot in
animal)
The tendency of infection to limfocyte CD4+
Sexual intercourse infection, blood, breast-
feeding
Leukemia: only 1% of all infected person after
latent period of 20-30 years
7/29/2019 carcinogenesis cqrcinogenic agents 2010
36/39
28/11/2005 tums-pafkugm 36
Retrovirus
HTLV-1
Is a lymphotrophic agent
7/29/2019 carcinogenesis cqrcinogenic agents 2010
37/39
28/11/2005 tums-pafkugm 37
Helicobacter pylori
Carcinoma
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 cases
Infection
Only 20-30% : ulcers
7/29/2019 carcinogenesis cqrcinogenic agents 2010
38/39
28/11/2005 tums-pafkugm 38
Helicobacter pylori
The strain causing disease contain pathogenic islandcontaining CagA (cytotoxin associated gene A) andsecretory system injects the CagA protein into thehost cells
Gene associated with virulence: VacA (encodevacuolated 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)
7/29/2019 carcinogenesis cqrcinogenic agents 2010
39/39
28/11/2005 t fk 39
Gastric Lymphoma(mucosal associated lymphoid tissue / MALT MALTOMA)
-The B-cell that give rise to this tumor normally
reside in the marginal zone marginal zonelymphoma
-Infection lymphoid infiltrates B-cells actively
proliferate may acquire genetic abnormalities
such as 11;18 translocation