Sigit Purbadi

 To understand the multistep process of carcinogenesis.

 To name the different factors that act in carcinogenic
process.
 To be able to differentiate between the different
carcinogens and their actions.
 To know the Clinical application due to Carcinogenesis

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 Oncogenesis: Pathogenesis of neoplasm
 Carcinogenesis: Pathogenesis of cancer
 Carcinogen - agent causing cancer.
 Oncogen - agent causing neoplasm.
 Mutagen - agent causing mutation.
 Oncogenes – genes causing cancer
 p-onc, v-onc, c-onc – Proto/viral/cell - naming of
oncogenes.

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Stage of initiation
Latent stage
Stage of promotion
Stage of malignant transformation

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 Bind on to DNA.
If the altered base is not removed before the
DNA replicates then the “wrong” base may be
inserted in the newly strand.
 Cause dimerisation of thymidine residues
 Cause single stranded breaks
 Cause double stranded breaks which may result
in translocations

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 Act as mitogens causing tissue enlargement.
These may be split into two types
◦ Small hydrophobic molecules such as
phenobarbitone or clofibrate which bind to
nuclear receptors
◦ Trophic hormones and growth factors
 Interact with components of the signalling
pathways, for example phorbol esters mimic
diacylglycerol activating protein kinase C
 Cause chronic damage to the tissue

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In most cases it would appear that the
mutated cell does not divide
spontaneously any more that the
normal cell. If, however, a mitogen
(the promoter)is present then the
mutant cells tend to divide before the
normal one. Timing, however, is of
the essence

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Proto-oncogene

Oncogene
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 Human Papilloma Virus
◦ Cervical neoplasia – warts, Cervical Cancer

 Epstein-Barr virus –
◦ Burkitts Lymphoma, Nasopharyngeal ca.

 Hepatitis B & C virus

◦ Hepatocellular carcinoma.

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Cancers are associated with the products of two viral genes called E6 and E7.
E6 binds to and inactivates p53, E7 binds and inactivates Rb. E6 and E7 can
transform cultured cells synergistically, those from low risk strains cannot.

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Cervical Cancer Early Detection

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 New technologies

• P16ink4a
– Cyclin-dependent kinase inhibitor whose expression is negatively
controlled by pRB gene product
– Strongly over-expressed in cervical cancer cell lines in which RB has
been iinactivated by the high-risk HPV E7 oncoprotein
– P16 overexpression, recognised by immunostaining, is a marker of HPV
infection and activated expression of viral genes and viral-induced
deregulation of cell cycle
– May be expressed in metaplastic, atrophi and endocervical cells
leading to loss of specificity
– Main clinical utility appears to be in triage of LSIL or for women HPV
DNA positive
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 New technologies

• mRNA expression of E6/E7 transcripts

– Persistent expression of viral oncogenes E6 and E7 necessary
step in HPV-induced oncogenesis
– Detection of E6/E7 mRNA for high risk types of HPV may be an
indicator of infection and of a further step in progression
towards cancer
– Main clinical utility will be to increase specificity
– Commercial kit PreTect HPV-proofer

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 Type I (70-80%)
1. Mutation Kras proto-Oncogene
2. Mismatch repair gene
3. Beta catenin gene
4. PTEN

 Type II UPSC/Clear cell(10-20%)

1. P53
2. Her2-Neu

Liu FS.Taiwan Jobstet Gynecol. 2007;46(1): 26-32

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Still Unknown

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 Know well the carcinogenesis process

 Do what you have to do

 Do what you can do

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Clinical Application
Normal

Oncogen
Chemoprevention
Vaccination Suppresor gen

Apoptosis gen
Growth factor
Repair gen
Receptor
Gynecologic
Transduction Cancer
signal Immunity
Nuclear factor Invasive

Metastasis

Survival 22
Tumour characteristics and environment promote VEGF
expression

IGF-1 PDGF
H2O2
EGF

IL-8
Binding and activation
bFGF VEGF release of VEGF receptor

Hypoxia 
COX-2 
NO 
Oncogenes 
P– –P

Increased expression P– –P

(MMP, tPA, uPA, uPAr,

eNOS, etc.) Survival Proliferation Migration
Permeability
ANGIOGENESIS

IGF = insulin-like growth factor; PDGF = platelet-derived growth factor

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