Carcinogenesis Flashcards
what are the four main categories of carcinogens
- chemicals
- radiation
- some parasites and fungal toxins
- viruses
chemical carcinogenesis the four stages
- initiation
- promotion (reversible)
- progression (irreversible)
- malignancy
Initiation
this is a mutagenic event involves cellular genome mutations in tumour suppressor genes and oncogenes
promotion
- this is NOT mutagenic
stimulates proliferation and causes both mutated and normal cells to proliferate
TPA
dioxin
Progression
irreversible enhancement/repression of gene expression
Selection of neoplastic cells for optimal growth genotype/phenotype in response to the cellular environment
High dose of carcinogen
tumours develop (carcinogen acts as both initiator and promotor/accelerator)
Low dose of carcinogen
no tumour develops
multiple doses of promotor
no tumour develop
low dose carcinogen + promotor
tumours develop
occupational exposure examples
chimney sweeps
dye industry and bladder cancer
dye industry and bladder cancer
carcinogen = 2-napthylamine
this requires activation
- LIVER = Converts 2NTA to carcinogenic metabolite 2-amino-naphthol
- this is then detoxified to gluronide which is excreted by the kidneys
BLADDER = urothelial cells express beta-glucuronidase
- this converts glucuronide to a carcinogen
asbestos exposure
increasing the risk by a factor of five
Risk depends on the duration and intensity of exposure
(1:50) in smokers
When inhaled, the needle-like fibres become coated in proteins (asbestos bodies) and their presence excites a macrophage and giant cell response, rather like silicosis
Cigarette smoking and cancer
1 : 22 increased lung cancer risk
- K-Ras and p53 are the two genes most frequently mutated in smoking- related lung cancers
- Cells treated with Benzopyrene show the same spectrum of mutations as found in the K-Ras and p53 of smokers.
GUANINE MUTATIONS
Carcinogen in tobacco smoke
hydrocarbon 3,4-benzpyrene which is then converted to Aryl Hydrocarbon Hydroxylase (AHH) and then into Benzoapyrene diol epoxide that binds to DNA forming damaging products
what detoxifies carcinogens
Glutathione S transferase (GSTM1)
Risk from carcinogens in diet
Gut bacteria convert nitrites and nitrates
Nitrosamines – carcinogens that can lead to cancers of gastro-intestinal tract and liver
Aflatoxicosis
Aflatoxicosis is poisoning, especially of the liver
that results from ingestion of aflatoxins from contaminated food.
- Aflatoxin B1 is a potent carcinogen in both human and animal species
Why is there such a large difference between cases of small and large intestine cancer
Bcl2 (which is expressed in the colonic epithelium but not small intestine) increased expression suppresses apoptosis increases cell survival
UV radiation
- Non-ionising (causes excitation of atoms)
- Damage DNA
- Form pyrimidine dimers but can also break DNA by indirect mechanisms
- Caucasians susceptible to melanoma and basal cell carcinoma
Radiation carcinogenesis
- Necroses and skin cancers were common amongst early radiologists before the risks were appreciated
- X-ray sources were used with total lack of protection
