2. Definition of Carcinogenesis and Carcinogen.
• Carcinogenesis / Oncogenesis / Tumorigenesis
means mechanism of induction of tumours
(pathogenesis of cancer).
• Agents which can induce tumours are called
carcinogens (etiology of cancer).
3. NORMAL CELLS CANCER CELLS
CARCINOGENESIS
Carcinogenic agent
Mutations/
chromosomal translocation
4. Etiology and pathogenesis of cancer can be
discussed under following 3 headings:
1. Chemical carcinogens and Chemical
Carcinogenesis.
2. Physical carcinogens and Physical
Carcinogenesis.
3. Biologic carcinogens and Viral Oncogenesis.
6. Chemical Carcinogens:
• Depending upon the mode of action of carcinogenic chemicals,
they are divided into 2 broad groups:
A. INITIATORS B.PROMOTERS
CHEMICAL CARCINOGENS
1. DIRECT-ACTING
CARCINOGENS
These carcinogens don't
require any metabolic
conversion to become
carcinogenic.
They directly damage the DNA
causing mutations
2. INDIRECT-ACTING
CARCINOGENS
These are chemical
Substances which require
prior metabolic activation
before becoming potent
‘ultimate’ carcinogens.
Lack the intrinsic
carcinogenic potential but
their application
subsequent to initiator
exposure helps the
initiated cell to proliferate
further.
7.
8. A. INITIATORS
I. DIRECT-ACTING CARCINOGENS:
i) Alkylating agents:
a) Anti-cancer drugs (e.g. cyclophosphamide,
chlorambucil)
b) β-propiolactone
c) Epoxides
ii) Acylating agents
a) Acetyl imidazole
b) Dimethyl carbamyl chloride
10. • Alkylating agents are compounds that work by
adding an alkyl group to the guanine base of the DNA
molecule.
• This causes breakage of the DNA strands, affecting
the ability of the cancer cell to multiply.
16. STAGES IN CHEMICAL CARCINOGENESIS/
PATHOGENESIS OF CHEMICAL CARCINOGENESIS:
• The induction of cancer by chemical carcinogens occurs after a
delay—weeks to months in the case of experimental animals,
and often several years in humans.
• Factors that influence the induction of cancer are the:
- Dose and Mode of administration of carcinogen.
- Individual susceptibility.
- Various predisposing factors.
17. • Chemical carcinogenesis occurs by induction of
mutation in the Proto-oncogenes and Anti-
oncogenes.
• Chemical carcinogenesis can be learned in three
steps:
1. INITIATION OF CARCINOGENESIS
2. PROMOTION OF CARCINOGENESIS
3. PROGRESSION OF CARCINOGENESIS
18. • Pathogenesis is different with direct and
indirect carcinogens.
1. INITIATION OF CARCINOGENESIS:
DIRECT CARCINOGENS
(ELECTRONPHILIC)
DNA Damage.
INDIRECT CARCINOGENS
(INACTIVE FORMS)
Activation
in liver
ACTIVE CARCINOGENS DNA
Damage.(ELECTRONPHILIC)
19. INDIRECT CARCINOGENS / PROCARCINOGENS
METABOLIC ACTIVATION
in liver by the mono-oxygenases
of the CYTOCHROME P-450
AFTER METABOLISM IN LIVER
THEY BECOME ELECTRON-DEFICIENT
AND ACT AS ELECTROPHILES
REACTIVE ELECTROPHILES BIND TO ELECTRON-RICH
PORTIONS OF OTHER MOLECULES OF THE CELL SUCH
AS DNA, RNA AND OTHER PROTEINS.
20. TARGET OF ELECTROPHILES
IS DNA, PRODUCING MUTAGENESIS.
IF THE CELL CONTAINING DAMAGED DNA IS NOT
REPAIRED AND IT UNDERGOES AT LEAST ONE CYCLE OF
PROLIFERATION.
Progeny of cells from mother cells will have
DNA damage which will be PERMANENT
and IRREVERSIBLE
21. DIRECT CARCINOGENS
DIRECTLY ACT AS REACTIVE
ELECTROPHILES AND BIND TO
ELECTRON-RICH PORTIONS OF OTHER
MOLECULES OF THE CELL SUCH AS
DNA, RNA.
22. NOTE:
•Any gene may be the target molecule in the
DNA for the chemical carcinogen.
•It has been observed that most frequently
affected Genes are RAS gene mutation and p53
gene mutation
23. 2.Promotion of Carcinogenesis
• Promotion is the next sequential stage in the chemical
carcinogenesis.
• Promoters of carcinogenesis are substances such as
- Phenols,
- Hormones,
- Artificial Sweeteners
- Drugs like Phenobarbital.
24. They differ from initiators in the following
respects:
i) They do not produce sudden change.
ii) The change induced may be reversible.
25. iii) They do not damage the DNA per se and are
thus not mutagenic but instead enhance the effect
of direct-acting carcinogens or indirect
carcinogens.
iv) Tumour promoters act by further clonal
proliferation and expansion of initiated
(mutated) cells, and have reduced requirement of
growth factor, especially after RAS gene
mutation.
26. 3. Progression of Carcinogenesis
• Progression of cancer is the stage when mutated
proliferated cell shows phenotypic features of
malignancy.
• These features pertain to morphology, biochemical
composition and molecular features of malignancy
• The new progeny of cells that develops after such
repetitive proliferation inherits genetic and
biochemical characteristics of malignancy.
29. • Various biological agents like VIRUSES,
PARASITES, FUNGI, BACTERIA are
implicated in etiology of cancer.
• However, the role of viruses in the causation
of cancer is more significant.
• Therefore, biologic carcinogenesis is largely
viral carcinogenesis.
30. EXAMPLES OF BIOLOGICAL CARCINOGENS:
BIOLOGICAL
CARCINOGENS
VIRUSES
1. HPV
2. EBV
3. ADENOVIRUS
4. HBV
BACTERIA
like
HELICOBACTER
PYLORI
FUNGUS
like
ASPERGILLUS
FlAVUS
PARASITES
like
SCHISTOSOMA
HAEMATOBIUM
31. ONCOGENIC VIRUSES :
• 20% of all cancers worldwide are due to
persistent virus infection.
Oncogenic viruses are of two types:
1. DNA oncogenic viruses.
2. RNA oncogenic viruses.
32. DNA Oncogenic Viruses.
VIRUS ASSOCIATED TUMOUR
1. PAPOVA VIRUS
• HUMAN PAPILLOMA
VIRUSES (HPV)
•Cervical cancer and its precursor lesions
•Papillomas (warts) on skin, larynx, genitals
(genital warts)
2. HERPES VIRUS
• EPSTAIN BAR VIRUS (EBV)
• HUMAN HERPES VIRUS 8
•Burkitt’s lymphoma.
•Kaposi’s sarcoma
3. POXVIRUSES •Molluscum contagiosum.
4. HEPADNAVIRUSES
• HEPATITIS B VIRUS (HBV) •Hepatocellular carcinoma
37. VIRAL ONCOGENESIS:
• General mode of oncogenesis by DNA and
RNA oncogenic viruses is briefly discussed as
below
1. Mode of DNA viral oncogenesis
2. Mode of RNA viral oncogenesis
38. 1. Mode of DNA Viral Oncogenesis:
• Host cells infected by DNA oncogenic viruses
may have one of the following 2 results:
I) REPLICATION II) INTEGRATION
The virus may replicate in the
host cell with consequent lysis
of the infected cell and release
of virions
The viral DNA may
integrate into the host
cell DNA
NO NEOPLASTIC
TRANSFORMATION &
DEATH OF CELL
NEOPLASTIC
TRANSFORMATION
BY INDUCING
MUTATION IN DNA
39.
40. 2. Mode of RNA Viral Oncogenesis:
• All oncogenic RNA viruses are retroviruses.
• A retrovirus is a type of RNA virus that inserts a
copy of its genome into the DNA of a host cell
that it invades, thus changing the genome of that
cell.
• Retroviruses contain two identical strands of RNA
and the enzyme, reverse transcriptase.
42. Step 1. The RNA virus invades the host cell. The viral
envelope fuses with the plasma membrane of the host
cell; viral RNA genome as well as reverse
transcriptase are released into the cytosol.
Step 2. Reverse transcriptase acts as template to
synthesize single strand of matching viral DNA
which is then copied to form complementary DNA
resulting in double-stranded viral DNA (provirus).
43. Step 3. The provirus is integrated into the host
cell genome producing ‘transformed host cell.’
Step 4. Integration of the provirus brings about
replication of viral components which are then
assembled and released by budding.
44. • The provirus integrated into the DNA of the
host cell genome and may induce mutation
and thus transform the cell into neoplastic
cell.
46. Physical carcinogens are divided into 2 groups:
A. Radiation physical agents.
B. Non-radiation physical agents.
47. A. Radiation physical agents.
The two main forms of radiation carcinogens
which can induce cancer.
I. Ultraviolet (UV) light and
II. Ionising radiation
48. I. ULTRAVIOLET LIGHT
• The main source of UV radiation is the sunlight;
others are UV lamps and welder’s arcs.
50. Epidemiology:
• In humans, excessive exposure to UV rays can
cause various forms of skin cancers:
Squamous Cell Carcinoma,
Basal Cell Carcinoma.
Malignant Melanoma
51. • High incidence of these skin cancers are seen in
Fair-skinned Europeans,
Albinos who do not tan readily,
Inhabitants of Australia and New Zealand
Living close to the equator who receive more sunlight,
and
Farmers and outdoor workers due to the effect of
actinic light radiation.
52. Mechanism of Carcinogenesis by UV light:
• UV light penetrates the skin for a few
millimeters only so that its effect is limited to
epidermis.
• The efficiency of UV light as carcinogen
depends upon the extent of light-absorbing
protective melanin pigmentation of the skin.
53. UV radiation may have various effects on the cells.
• The most important is
Induction of mutation.
• Others are:
Inhibition of cell division.
Inactivation of enzymes.
Cell death.
54. • The most important biochemical effect of UV radiation is the
formation of pyrimidine dimers in DNA.
Formation of thymine
dimer lesion in DNA.
The photon causes
two consecutive
bases on one strand
to bind together,
destroying the normal
base-pairing double-
strand structure in
that area.
55. • Like with other carcinogens, UV radiation also
induces mutated forms of oncogenes (in particular
RAS gene) and anti-oncogenes (p53 gene).
56. II. IONIZING RADIATION
• Ionizing radiation is any type of particle or electromagnetic wave
that carries enough energy to ionize or remove electrons from an
atom.
• Examples of IONIZING RADIATION which can ionize atoms:
X-rays
Alpha rays (emitted by radioactive Uranium, Radium)
Beta rays (emitted by decaying nuclear fuel)
Gamma-rays (Sun, Nuclear explosions).
Protons
Neutrons
57. Epidemiology:
• Most frequently, ionization radiation-induced
cancers are
All forms of Leukaemias (except CLL);
Others are cancers of the thyroid (most commonly
papillary carcinoma), skin, breast, ovary, uterus,
lung, myeloma, and salivary glands.
58. Evidences in support of carcinogenic
role of Ionizing radiation in cancers
• Miners in radioactive elements have higher
incidence of cancers.
59. • Accidental leakage at nuclear power plant in 1985
in Chernobyl (Ukraine) has caused long-term
hazardous effects of radioactive material to the
population living in the vicinity.
60.
61. • Japanese atom bomb survivors of the twin cities of
Hiroshima and Nagasaki after World War II have
increased frequency of malignant tumours, notably
acute and chronic myeloid leukaemias, and various
solid tumours of breast, colon, thyroid and lung.
62. • High incidence of Osteosarcoma was observed in
young American watch-working girls (RADIUM
GIRLS) engaged in painting the dials with luminous
radium who unknowingly ingested radium while
using lips to point their brushes
63. Mechanism of carcinogenesis by Ionizing Radiation
• Mechanism Radiation damages the DNA of the
cell by one of the 2 possible mechanisms:
i) It may directly alter the cellular DNA.
ii) It may dislodge ions from water and other
molecules of the cell and result in formation of
highly reactive free radicals that may bring
about the damage.
64.
65. • Damage to the DNA resulting in mutagenesis
is the most important action of ionising
radiation.
• It may cause chromosomal breakage,
translocation, or point mutation.
66. The effect depends upon a number of factors such as
- Type of radiation,
- Dose & Dose-rate,
- Frequency and
- Various host factors such as
Age, Individual Susceptibility, Immune
Competence, Hormonal Influences And Type Of
Cells Irradiated
67. B. Non-Radiation Physical Agents.
• Mechanical injury to the tissues or prolonged
contact with certain physical agents has been
observed to have higher incidence of certain
cancers.
68. Examples (Rare).
1. GALLSTONES: Stones in the gallbladder and in
the urinary tract having higher incidence of cancers
of these organs.
69. 2. Healed scars: Healed scars following burns or
trauma for increased risk of carcinoma of
affected skin.
70. 3. ASBESTOSIS: Occupational exposure to
asbestos (asbestosis) associated with
asbestos-associated tumours of the lung and
malignant mesothelioma of the pleura.
71. 4. Workers engaged in hardwood cutting or
engraving having high incidence of
Adenocarcinoma of paranasal sinuses
