Basic carcinogeneis ppt

1. CARCINOGENESIS
PRESENTED BY
N.NARMATHA CRRI

2. Introduction
Carcinogenesis or oncogenesis or tumorogenesis means mechanism of induction
of tumours.
Agents which can induce tumours are called carcinogens.
The pathogenesis of cancer is discussed under the following headings:
 Molecular carcinogenesis.
 Chemical carcinogenesis.
 Physical carcinogenesis.
 Biologic carcinogenesis.

3. MOLECULAR PATHOGENESIS OF CANCER
The mechanism as to how a normal cell is transformed into a cancer cell is comple
The general concept of molecular mechanism of cancer is briefly outlined below
Chemical carcinogens
Radiation
viruses
Genes affecting apoptosis
Activation of oncogenes
Inactivation of anti-oncogenes
Apoptosis regulating genes
Clonal expansion
Tumour progression
Normal cell mutated cell cancer cell malignant tumour
DNA damage
DNA repair
succesfull

4.  Monoclonality of tumours
 Field theory of cancer
 Multi step process of cancer growth and progression
 Genetic theory of cancer
 Genetic regulators of normal and abnormal mitosis.
Monoclonality of tumours: There is strong evidence to support that most human cancers arise
from a single clone of cells by genetic transformation or mutation.
Eg: In a case of multiple myeloma there is production of a single type of immunoglobulin or its
chain.
Field theory of cancer: In an organ developing cancer ,in the backround of normal cells, limited
number of cells only grow into cancer after undergoing sequence of changes under the influence
of etiologic events – termed as ‘field effect’

5. Multi – step process of cancer growth and progression:
Carcinogenesis is a gradual multi-step process involving many generations of cells.The various ca
may act on the cell one after another(multi-hit process).The same process is involved in further
progression of tumour. Ultimately ,the cell so formed are genetically and phenotypically transform
cells having phenotypic features of malignancy-excessive growth, invasiveness and distant metast
Genetic theory of cancer:
cell growth of normal as well as abnormal type is under genetic control.
Inherited or Induced mutations
genetic abnormalities in cell genes with abnormal expression
cancer

6. Genetic regulators of normal and abnormal mitosis
In normal cell growth ,regulatory genes control mitosis as well as cell aging, terminating in ce
death by apoptosis.
Normal
proto-oncogenes
Anti-oncogenes
Apoptosis regulatory genes
DNA repair genes.
Cancer
Oncogene activation
Inactivation of cancer suppression genes
Abnormal apoptosis regulatory genes
Failure of DNA repair genes .

7. Major genetic properties or hallmarks of cancer.
EXCESSIVE AND AUTONOMOUS CELL GROWTH
REFRACTORINESS TO GROWTH INHIBITION
ESCAPING CELL DEATH BY APOPTOSIS
AVOIDING CELLULAR AGING
CONTINUED PERFUSION OF CANCER
INVASION AND DISTANT METASTASIS
DNA DAMAGE AND REPAIR SYSTEM
CANCER PROGRESSION AND TUMOUR
HETEROGENEITY
MULTISTEP MOLECULAR PHENOMENON
MICRORNA’s IN CANCER

8. CHEMICAL CARCINOGENESIS
The induction of cancer by chemical carcinogens occurs after a delay – weeks to months in
experimental animals and often several years in man. Basic mechanism of chemical carcinogene
is by induction of mutation in the proto-oncogenes and anti-oncogenes.
Other factors that influence the induction of cancer are the dose and mode of administration of
carcinogenic chemical, individual susceptibility and various predisposing factors.
Chemical Carcinogenesis involves 3 stages.
 Initiation
 Promotion
 Progression

9. Direct acting carcinogens Indirect
carcinogens(procarcinogens)
(alkylating agents,acylating agents) (polycyclic aromatic hydrocarbons,
aromatic amines,azo-dyes).
No metabolic activation Metabolic activation (liver-
mono-oxygenases of the
cytochrome P-450 system )
Target Cell
Reactive Electrophiles
Target Molecules(DNA)
permanent DNA damage
(initiated or mutated cell)
INITIATION
(permanent&
Irreversible)

10. Clonal proliferation of altered cells
Cancer phenotype
Malignant tumour
INITIATED OR MUTATED CELL
PROMOTION
(reversible)
PROGRESSION
It is also noted that persistent and sustained application/exposure of the cell to initiator alone
unassociated with subsequent application of promoter may also result in cancer.But the
vice versa does not hold true.

11. PHYSICAL CARCINOGENESIS
Physical agents in carcinogenesis are divided into 2 groups
Radiation non-radiation
Ultraviolet Ionising mechanical injury to the tissues
neutrons, Stones in the gall bladder, urinary
protons,α-,β-,x-rays tract, healed scars following burns or
trauma, asbestosis associated
tumours of the lung, implants of inert
material such as plastic, glass in
prosthesis
Initial exposure – Latency period(10-20yrs later)-Appearance of mutation
Also act as co-carcinogens.

12. ULTRA VIOLET LIGHT:
Source of UV radiation is the sunlight(main),UV lamps and welder’s arcs.
UV light penetrates the skin for a few millimetres only so that its effect is limited to epidermis.
Excessive exposure to UV rays can cause various forms of skin cancers-squamous cell ca,
basal cell ca, malignant melanoma.
MECHANISM
Induction of cell division
Inactivation of enzymes
Cell death.
Formation of pyrimidine dimers in DNA.
UV-induced DNA damage in the predisposed persons who are excessively exposed to
sunlight such damage remain unrepaired.
Eg: xeroderma pigmentosum is predisposed to skin cancers at younger age(20 yrs).

13. IONISING RADIATION
Radiation damages the DNA of the cell
Directly alter the cellular DNA Dislodge ions from water and other molecules
of the cell
Free radicals
Cell damage
Damage to DNA resulting in mutagenesis is the most important action of ionising radiation.
It may cause chromosomal breakage, translocation, point mutation.
Eg: Higher incidence of radiation dermatitis and subsequent malignant tumours of skin was note
in X-ray workers and radiotherapists .

14. BIOLOGIC CARCINOGENESIS
The epidemiological studies on different type of cancers indicate the involvement of transmissible
biologic agents in their development, chiefly viruses. Other biologic agents are
Parasites- schistosoma haematobium infection of urinary bladder is associated with high incidenc
of squamous cell carcinoma of the urinary bladder.
Clonorchis sinensis – cholangiocarcinoma
Fungus- aspergillus flavus( in stored grains) - aflatoxin – hepatocellular carcinoma
Bacteria- helicobacter pylori - gastric lymphoma and gastric carcinoma
Viruses(20%) –DNA oncogenic viruses (PAPOVA VIRUS,HERPES VIRUS,ADENOVIRUS,POX VIRUS,
HEPADNA VIRUS)
- RNA oncogenic viruses (HEPATITIS C VIRUS, MOUSE MAMMARY TUMOUR VIRUS ,HTLV-I,II)

15. DNA virus
envelop
T-gene
Host cell
T antigen
cell lysis
REPLICATION DNA virions INTEGRATION
STEP 1
STEP 2
STEP 3
STEP 4
DNA virus invades host cell
Viral DNA is incorporated into host nucleus
T-antigen is expressed immediately after infection
Replication of viral DNA. New virions assembled in the
Cell nucleus
New virions are released by host cell lysis.
MODE OF DNA VIRAL ONCOGENESIS

16. MODE OF RNA VIRAL ONCOGENESIS
RNA virus
Invades host cell
Viral RNA genome and reverse transcriptase released into cytosol
Reverse transcriptase act as a template to synthesise single strand of matching viral DNA
Viral DNA then copied to form complementary DNA
Double stranded viral DNA (pro virus)
INTEGRATION
Host cell genome
Transformed host cell
REPLICATION OF VIRAL COMPONENTS
Released by budding

17. CONCLUSION
Understanding about carcinogenesis will yield important advances for detecting high risk
patients, monitoring preventive interventions, and assessing cancer risks and
pharmacogenomics.
The survival of the patients remains very low mainly due to their high risk of developing
cancer.
Therefore, the early detection and prevention of cancer and pre-malignancy are quite
important.
This presentation thus focussed on the current understanding of carcinogenesis for the
early detection and prevention of malignancy.

18. Thank you