carcinogenesis mechanism # direct and indirect chemical agents# DNA and RNA viruses,bacterial and protozoal causes of carcinogenesis

1. CHEMICAL AND MICROBIAL
CARCINOGENESIS
Dr Y L S
.

2. INTRODUCTION
• Carcinogenesis or oncogenesis means mechanism of induction of
tumors.
• Agents which can induce tumors are called carcinogens.
• Cell division –physiological process occur in all cells.
• Homeostasis-balance between proliferating and programmed cell
death –tightly regulated process.
• Mutation in DNA disrupt the programming of regulation of the
process.
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4. Etiology and pathogenesis of cancer is discussed under the
following 4 broad headings-
1 Molecular pathogenesis of cancer{genes and cancer}
2 Chemical carcinogenesis
3 Physical carcinogenesis and radiational carcinogenesis
4 Biological carcinogenesis and viral oncogenesis
5 Hormonal carcinogenesis
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5. CHEMICAL CARCINOGENESIS
• Carcinogenesis is a multi step process and it include stages of
• 1) initiation of carcinogenesis
• 2) promotion of carcinogenesis
• 3) progression of carcinogenesis
• INITIATION-results from exposure of cells to a sufficient dose of
carcinogenesis agent ,an initiated cell is altered making it
potentially capable of giving rise to tumor.
• Initiator alone is not sufficient to cause tumor formation.
• Initiator causes permanent DNA damage and therefore it is rapid
and irreversible and has memory and tumors re produced even
several months after exposure of promoter agent.

6. • PROMOTERS- can induce tumors in intiated cells but they are non
tumorogenic by themselves.
• Tumors are not initiated when promoter agent is applied before
initiating agent
• This indicates that in contrast to the effect of initiators the cellular
changes produced by promoters donot effect DNA directly and are
reversible.
• Promoter enhances the proliferation of intiated cells an effect that
may contribute to development of additional mutations.
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8. • All initiators chemical carcinogens are highly reactive electrophiles
that can react with nucleophilic sites in the cells.
• Their targets are DNA,RNA and proteins and in some cases
interactions causes cell death. Initiation obviously causes inflicts non
lethal damage on DNA that cannot be repaired .the mutated cell
then passes on the DNA lesion to its daughter cells.
• Chemicals that can causes carcinogenesis can be classified into
directly acting agents and indirectly acting agents.
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10. DIRECTLY ACTING AGENTS
• Directly acting agents require no metabolic conversion to become
carcinogenic.
• Most of them are weak carcinogens but are important because
some are cancer chemotherupatic drugs that have successfully
cured, controlled or delayed recurrence of certain types of cancers
only to evoke later a second form of cancer usually AML.
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11. INDIRECTLY ACTING AGENTS
The designation indirectly acting agents refer to chemicals that require
metabolic conversion to an ultimate carcinogen before they become
active.
Some of the important carcinogens are polyclonal hydrocarbons mainly
from fossil fuels.
Example benzo pyrenes and other carcinogens are formed in high
temperature combustion of tobacco in cigarette smoking are
implicated in lung cancer.
The principle active products in many hydrocarbons are epoxides which
form covalent adducts with molecules in the cell principally DNA but
also with RNA and proteins.
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12. The aromatic amines and azo dyes are another class of indirect acting
carcinogens that were widely used in past in dyes and rubber
industries.
Most of chemical carcinogens require activation for conversion into
ultimate carcinogens.
Thus the carcinogenic potency of a chemical is determined not only by
inherent reactivity of its electrophile derivative but also by balance
between metabolic activation and inactivation.
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13. METABOLISM OF INDIRECTLY ACTING AGENTS
• Most of the known carcinogens are metabolised by cytochrome
p450 dependant mono oxygenase. The genes that encode these
enzymes are polymorphic .
• And the activity and inducibility of these enzymes are quite variable
in different individuals.
• Because these enzymes are essential for the activation of pro
carcinogens the suseptability to these carcinogenesis is regulated by
genes encoding this enzymes.
• Thus it may be possible to assess the cancer risk in given individual
by genetic analysis of such enzyme polymorphisms.
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14. CONT………
• The metabolism of polycyclic aromatic hydrocarbons such as benzo
pyrenes by product of p 450 gene,CYP1A1 provides an example.
• Atleast 10% white population has highly inducible form of this
enzyme that is associated with increase risk in of lung cancers in
smokers.
• Light smokers with suseptable genotype CYP1A1 has seven folds
increased risk of developing lung cancer compared with smokers
without permissive genotype.
• Not all cancers are genetically determined but age ,sex, nutrition
also determine the internal dose of toxicants produced and hence
influence the risk of cancer development.
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15. MOLECULAR TARGETS OF CHEMICAL CARCINOGENS
• Majority of chemicals are mutagenic ,malignant transformation
occur due to these mutations.
• Thus DNA is a primary target for chemical carcinogens there is no
single or unique alteration associated with initiation of
carcinogenesis.
• The commonly mutated oncogenes are tumor suppressor genes
such as RAS and p53 are particularly important.
• A very good example is that aflatoxins B1 a naturally occurring agent
produced by some strains of aspergillus which grows in improperly
produced grains and nuts.
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16. • Thus there is strong correlation between dietary level of this food
contaminents and the incidence of hepatocellular carcinoma.
• Interestingly aflatoxin B produce mutation in p53 gene 90% of these
mutations are characteristics GC---TA transversion in codon 249.
• By contrast p53 mutations are less frequent in liver tumours from
the areas where risk of from these aflatoxin contamination is less
frequent.
• Thus the detection of the signature mutations with in p53 gene
establishes aflatoxin as a causative agent
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17. • These associations are proving to be useful epidemiological studies
of chemical carcinogenesis.
• Additionally vinyl chloride ,arsenic, nickel, chromium insecticides,
fungicides and polychlorinated biphenyls are potential carcinogens
at work place and home.
• Nitrates used as food preservative causes nitrosylation of amines
and thus considered t be carcinogenic.
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19. INITIATION AND PROMOTION OF CHEMICAL CARCINOGENESIS
• Unpaired alterations in DNA is first step for process of initiation .For
this change to be heritable the damaged DNA templete must be
replicated.
• Thus for initiation to occur carcinogenic cell must undergo atleast
one cycle of proliferation so that the change in DNA will get fixed.
• In liver many chemicals are activated to reactive electrophiles yet
most of them donot produce cancer until the liver cells proliferate
and with in few days of formation of DNA adducts.
• The mitogenic stimulus may be provided by carcinogen itself
because may cells die as a result of toxic effect of carcinogenical
chemical there by stimulating regeneration in surviving cells.
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20. • Alternatively cellular proliferation may be induced by biological
agents such as viruses and parasites dietary exposure or hormonal
influences.
• Agents which do not cause mutations instead stimulate the division
of mutated cells are known as promoters
• Application of promoter leads to proliferation of and clonal
expansion of intiated cells .
• Such cells will have reduced growth factors requirement and may
also be less responsive to growth inhibitory signals in the
extracellular milieu.
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21. Driven to proliferate the initiated clone of cells suffer additional
mutations developing eventually into malignant tumour.
Thus the process of tumor promotion include multiple steps-
Proliferation of preneoplatic cells
Malignant conversion
Tumor progression
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22. Viral oncogenesis
• General aspects
• In general persistence of DNA or RNA viruses may induce
mutations in the target host cell.
• Persistence of DNA or RNA viral infection causes activation of
growth promoting pathways or inhibition of tumor suppressor
products in the infected cells.

23. • Mode of DNA oncogenesis
• host cells infected with by DNA oncogenic viruses may have one of
the 2 following results
• Replication-the virus may replicate in the host cell with consequent
lysis of the infected cell and release of virions.
• Integration-the viral DNA may integrate into the host cell DNA results
in inducing mutation –neoplastic transformation of the host cell.
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26. • MODE OF RNA VIRAL ONCOGENESIS
• RNA viruses contain 2 identical Strands of RNA and the enzymes,
reverse transciptase
• reverse transcriptase –act as templete to synthesise a single strand
of form another strand of complentary DNA-PROVIRUS
• The provirus is then integrated into the DNA of the host cell genome
and may induce mutation and thus transform the cell into
neoplastic cell.
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27. • Retroviruses are replicated competent. the host cells which allow
replication of integrated retroviruses.
• Viral replication begins after integration of the provirus into host
cell genome.
• Transcription of proviral genes translated to components of virus
particles-reassembles –buds off

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30. HUMAN PAPILLOMA VIRUSES
• Benign forms of HPV include 1,2,4 ,7 causes benign squamous
papillomas whereas HPV 16 and 18 are implicated in cancers
particularly in SQC and ano genital cancers and 20% of
oropharyngeal cancers.
• Genital warts have low potential for malignant transformation
mostly caused by HPV 6 and HPV 11. HPV genome is maintained in
non integrated epithelial forms.
• While in cancers HPV genome is integrated in to host genome
suggesting that this integration is important for malignant
transformation.
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31. • Since the integration site is random there is no consistent
association with host proto oncogene.
• The oncogenic potential of HPV can be related to products of two
viral genes E6 and E7 they interact with variety of growth regulating
proteins tumor suppressor genes
• The E7 protein bind to RB protein and displaces E2F transcription
factors promoting progression through the cell cycle.
• E7 also inactivate CDKI p21 and p27 E7 protein from the high risk
HPV types also bind and activate cyclin E and A.
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32. • E6 protein binds to and mediates the degradation of p53 and BAX,
pro apoptotic member of BCL2 family and activates telomerase
• E6 p53 interaction may offer some clues regarding polymorphism
and risk factors for development of cervical cancers.
• The p53 arg 72 variant is much more susceptible to degradation by
E6 and much more likely to develop cervical carcinoma.
• To summarize high risk HPV types express oncogenic proteins that
inactivates tumor suppressors ,activate cyclins, inhibits apoptosis
and combat cellular sensence.
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33. • How ever only infection with HPV is itself is not sufficient for causing
cancer.For example interaction of hpv with human keratinocytes
itself do not cause cancer ,transfection with a mutated RAS gene
results in full malignant transformation.
• In addition to genetic factors risk factors like smoking, microbial
infection dietary deficiencies and hormonal changes are all
implicated in pathogenesis of cervical cancer.
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35. EBSTEIN BARR VIRUS
• EBV a member of herpes is implicated in pathogenesis of many
human cancers including
• burkitt lymphomas,
• B cell lymphomas {in IC patients and HIV patients}
• nasopharyngeal carcinomas
• subset of hodkins lymphomas
• gastric carcinomas
• rarely T cell lymphomas and NK cell lymphomas.
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36. • EBV infect B lymphocytes and uses the complementary receptor CD
21 to attach and infect B cells. this infection is latent and there is not
viral replication and cells aquire the ability to propagate indefinitely
invivo.
• One EBV gene LMP-1 act as an oncogene which act as an activator
of CD 40 receptor on TH cell and induce B cell growth.
• LMP 1 also activate NF KB and JAK STAT signaling pathway and
promote B cell survival and proliferation.
• LMP 1 prevents apoptosis by activating BCL2.
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38. • HEPATITIS B AND C VIRUSES
• 70-80% HCC are due to hepatitis B and C .The HBV and HCV
genome do not encode any viral oncogenes and although the
HBV DNA is integrated within human genome there is no
consistent pattern of integration into liver cells.
• The oncogenic effect of these viruses are multifactorial dominent
effect is due to chronic inflammation with hepatocyte death and
regeneration and genomic damage.
• In the setting of unresolved chronic inflammation as occur in h
pylori, the tumor response become maladaptive promoting
tumorogenesis.

39. • With the ongoing hepatocellular damage chronic viral infection
leads to compensatory proliferation of hepatocytes aided and
abetted by release of GF ,cytokines, chemokines that will activate
immune system for cell survival angiogenesis and tissue
remodelling.
• These immune cells also produce reactive oxygen species that are
genotoxic and mutagenic.
• One key step is activation of NF kB pathway within hepatocytes
which blocks apoptosis mechanism increase genotoxic stress in
regenerating hepatocytes.
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40. • HBV contains a gene known as HBx gene that directly or indirectly
activate variety of transcription factors and several signal
transduction factors mechanism
• HCV although not a DNA virus has less well defined mechanisms to
explain tumourogenesis.
• in addition to ongoing hepatocellular damage and compensatory
proliferation HCV core protein have direct effect on tumorogenesis
possibility by activating variety of growth promoting signal and
transduction pathway.
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42. HELICOBACTER PYLORI
H pylori is first bacteria to be classified as carcinogen.it is implied in
carcinogenesis of both adenocarcinoma and lymphomas.
It is involved in increase in epithelial cell proliferation ’in background of
chronic inflammation. there is initial development of chronic gastritis
and gastric atrophy ….intestinal metaplasia ….dysplasia and cancer
Strains which contain Cag A gene are responsible for penetration into
gastric epithelial cell and initiate signal cascade that mimics
unregulated growth factor stimulation.
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43. • H pylori is known for development of gastic lymphomas and they
are of B cell origin and because tumour resembles some of the
features of payers patch they are often called MALTomas.
• H pylori infection leads to appearance of reactive T cells which in
turn leads to proliferation of B cells .these cells grow into
monoclonal MALTomas tht remain dependent on T cell activated
Bcell proliferation ,this stage can be cured with antibiotic therapy.
• In later stages additional mutations may be acquired with 11,18
translocation that causes NF KB activation continuously leading to
spread of tumour beyond stomach.
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45. OTHER BACTERIA ASSOCIATED WITH CARCINOGENESIS
Salmonella typhi associated with gall bladder cancer
Streptococcus Bovis associated with colorectal cancer
Chlamydia pneumoniae associated with lung cancer
Mycoplasma have role in different types of cancers.
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46. PARASITES IN CARCINOGENESIS
SCYSTOSOMA HAEMATOBIUM-BLADDER CANCER
Fibrosis by eggs ----proliferation-----hyperplasia-----metaplasia
Increase in levels of b glucoronidase by parasite liberates amines in
urine
SCYSTOSOMA JAPONICUM-COLORECTAL AND HEPATOCELLULAR
CANCER
Soluble egg antigen evokes chronic inflammation and p53 mutations
products derived from parasites causes genetic instability
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47. • CHLORENCHIS SINENSIS-CHOLANGIOCARCINOMA
• Endogenous nitrosation formation and accumulation of these
substances around bile duct evokes chronic inflammtion hyperplasia
and adenomatous changes of bile duct epithelium
• O VIVERENI AND O FELINEUS-CHOLNGIOCARCINOMA
• The products which are formed after endogenous nitrosation is a
DNA methylation product results in dna damage ----bile duct
proliferation
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48. TRICHOMONAS VAGINALIS -CERVICAL INTRA EPITHELIAL NEOPLASIA
The presence of cell detached product involved in cytopathic effect and
low acidic ph produced by metabolic products responsible for CIN
TAENIA SOLIUM-GLIOBLASTOMA MULTIFORMAE AND HEMATOLOGICAL
DISORDERS
NO released by chronic inflammation and inhibition of tumour
suppressor genes
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