CARCINOGENESIS
Carcinogenesis
• “Creation of cancer”
• The process by which normal cells are
transformed into cancer cells.
Carcinogenic Agents
• Chemical carcinogens
• Radiant energy
• Oncogenic viruses
• Other microbes
‘John Hill observed nasal polyps in snuff users’
Sir Percival Pott
LUDWIG REHN - Aromatic amines & bladder cancer
Chemical Carcinogenesis
• Multistep process
• 2 major events
- Initiation
- Promotion
Initiation
• Process by which carcinogenesis begin
• Chemicals – Initiators
• Natural or synthetic products
• 2 categories
- Direct acting
- Indirect acting
Chemical Carcinogens
DIRECT ACTING INDIRECT ACTING
ALKYLATING AGENTS AROMATIC HYDROCARBONS
β-propionolactone Benzanthracene
Dimethyl sulfate Benzopyrene
Diepoxybutane 3-methyl chloranthrene
Anticancer drugs 7, 12- Dimethyl benzanthracene
ACYLATING AGENTS AROMATIC AMINES, AMIDES, AZO DYES
1-acetyl imidazole β-naphthylamine
Dimethylcarbamyl chloride Benzidine
2-acetylaminofluorene
Dimethyl aminoazobenzene
(butter yellow)
NATURAL PLANTS & MICROBIAL PRODUCT
Aflatoxin B1
Griseofulvin
Cycasin
Safrole
PROMOTION
• Process by which carcinogenicity of chemicals
is augmented
• Promoters
• Eg:- Phorbol esters, hormones, phenols etc
• Nontumorigenic
• Sufficient dose of initiator needed
• Initiated cell is altered
• Initiation alone is not enough
• Causes mutation (rapid & irreversible & has
memory)
• Promoters induce tumours in initiated cells
• Promoters cause reversible changes
INITIATOR PROMOTER
MECHANISM Induction of mutation Not mutagenic
DOSE Single for a short time Repeated doses for long
RESPONSE Sudden Slow
CHANGE Permanent, irreversible Reversible
SEQUENCE Applied first After initiator
EFFECTIVITY Effective alone Not effective alone
MOLECULAR CHANGE RAS, p53 mutations Clonal expansion of
mutated cells
EXAMPLE Most chemical carcinogens Hormones, phorbol esters
AME’S TEST- Mutagenic potential
Salmonella typhimurium
Radiation Carcinogenesis
• Ultraviolet rays
UVA (320-400 nm)
UVB (280-320 nm) SCC SCC
BCCBCC
Melanoma
Melanoma
UVC (200-280 nm)
• Degree of risk depends on
-type of UV rays
- intensity of exposure
- quantity of melanin in skin
• UVB →Pyrimidine dimers in DNA
Xeroderma pigmentosum
• Autosomal recessive
• Extreme photosensitivity
• 2000 fold increased risk for skin cancer
• Inherited inability to repair UV induced DNA
damage
Ionizing Radiation
• Electromagnetic (x rays, γ rays)
• Particulate (α , β, protons, neutrons)
• Sources – Medical or occupational exposure
- Nuclear plant accidents
- Atomic bomb explosions
MICROBIAL CARCINOGENESIS
• Viruses
- DNA :- HPV, EBV, Hepatitis B, KSHV
- RNA :- HTLV 1
• Bacteria :- Helicobacter pylori
• Parasites :- Schistosoma hematobium,
Clonorchis sinensis
HPV
• 1, 2, 4, 7 – Benign squamous papillomas
• 16, 18 (MC)
• 31, 33, 35, 51 - Sq cell Ca cervix
• 6, 11 - Genital warts
• Viral DNA integration is important for
malignant transformation
DNA Handling Genes
LCR/
Ori E6
E7
7904/1
L1
7000 1000 •DNA replication
(viral helicase)
6000 2000 E1
5000 3000
L2 4000
E4
E2
•Transcriptional regulation
E5 •recruit E1 to Ori,
•genome segregation
during cell division
Oncogenes
•inactivate cellular p53 •inactivate cellular pRb
E6
E7
•Together the viral 7904/1
oncogenes L1
7000 1000
immortalize the
cell and prime it
for viral DNA
6000 2000 E1
replication by
disrupting the cell
cycle. 5000 3000
L2 4000
E4
E2
E5
EBV
• African type of Burkitt lymphoma
• B cell lymphomas in immunosuppressed
• HL
• Nasopharyngeal Ca
RNA Oncogenic virus
• HTLV-1
• T cell leukemia/ Lymphoma
• Tropism for CD4+ T cells
HTLV 1 infection
↓(TAX)
Nonmalignant polyclonal cell population
↓(TAX)
Mutation & genomic instability
↓
Monoclonal neoplastic T cell population
H Pylori
Gastric adenocarcinoma
MALTomas
Cag A gene
Vac A gene
H Pylori infection
↓
Chronic gastritis
↓
Multifocal atrophy&↓ed gastric acid secretion
↓
Intestinal metaplasia, Dysplasia
↓
Carcinoma
