Carcinogenesis Flashcards
Identify the major categories of carcinogens.
- Chemicals (e.g. smoking)
- Radiation (e.g. UV, ionizing radiation)
- Some parasites and Fungal toxins (e.g. aflatoxin)
- Viruses
Describe the mechanism of chemical carcinogenesis.
- Initiation: Initiation (mutagenic) event involves cellular genome mutations in tumour suppressor genes and oncogenes, resulting in altered genotype of an ‘initiated’ cell. Involves a carcinogen.
- Promotion: Promotion (reversible, not mutagenic) Stimulates proliferation (clonal expansion) and causes both mutated and normal cells to proliferate, resulting in pre-neoplastic focal lesion. Involves a promoter.
- Progression: irreversible enhancement/ repression of gene expression. Selection of neoplastic cells for optimal growth genotype/ phenotype in response to the cellular environment
- Malignancy/ Cancer
Give an example of carcinogen and promoter.
Carcinogen:
-Methyl- cholanthrene
Promoter (accelerator)
- TPA (phorbol esters, present in Croton Oil)
- Dioxin (polycyclic aromatic compounds).
Discuss the impact on different doses of carcinogen and promoter on carcinogenesis.
- High dose of carcinogen: tumours develop (carcinogen acts as both initiator and promotor/accelerator)
- Low dose of carcinogen: no tumours develop
- Multiple doses of promoter: no tumours develop
- Low dose carcinogen + promoter: tumours develop
Define carcinogen.
a substance capable of causing cancer in living tissue.
Define initiator.
Substances that cause the initial changes or mutations in DNA (e.g. mutagens)
Define promoter.
Type of epigenetic carcinogen that promotes neoplastic growth only after initiation by another substance.
Define latent period.
Time between initiation and promotion event(/appearance of cancer)
What is the result of a short vs long latent period ?
No effect on frequency of tumour in population, affects rate at which tumor develops (shorter latent period = tumor develops more quickly)
Link the following with the tumour they induce and state where they may be found.
- Asbestos
- UVB
- Ionising radiation
- Aflatoxin
- Naphthylamine
- Benzpyrene
- Asbestos: Bronchogenic carcinomas (due to predisposition by asbestosis) + Mesothelioma (if exposure to ‘blue’ asbestos fibres)
- UVB: Multiple squamous and basal cell carcinomas, and melanomas
- Ionising radiation: Skin Cancer, Leukaemia, Bone Cancer, Thyroid Cancer (e.g. Thyroid Carcinoma)
- Aflatoxin: liver cancer (carcinoma)
- Naphthylamine (intermediate for dye manufaturing/antioxidant in the rubber industry ) : Bladder cancer
- Benzpyrene (in tar which is in soot): scrotal cancer + lung cancer (e.g. squamous cell carcinoma)
Outline the mechanisms of cancer induction in the bladder by napthylamine.
- Aromatic amines such as 2-naphthylamine are pre-carcinogens requiring activation
- Liver converts 2NTA to carcinogenic metabolite 2-amino-naphthol
- Detoxified to glucuronide (not carcinogenic)
- Excreted by kidneys
- In bladder, human urothelial cells express b-glucuronidase
- This converts glucuronide to a carcinogen
Describe the relationship between years after start of exposure to carcinogen and percentage with bladder cancer.
Less than 2 years: Longer onset time with low risk
3 to 4 years: Intermediate onset time with intermediate risk
More than 5 years: Short onset and high risk
Describe results of asbestos exposure.
- Asbestos is a fibrous silicate substance
- 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
MESOTHELIOMA
- Due to blue asbestos fibres
- Microscopically: dense white sheet of mesothelioma (arising in mesothelial cells) encircling the lung arising from the pleura
- The tumour extends only a little distance into the lung parenchyma (metastatic spread is uncommon)
- Mesothelioma is a bulky tumour that can fill the chest cavity
- 25 – 45 year latent period
- Depends on duration and intensity of exposure
e. g. risk is higher (1:50) in smokers as compared with non-smokers exposed to asbestos
BRONCHOGENIC CARCINOMAS
-Due to predisposition by asbestosis (formation of scar tissue in the lung as a result of exposure) which increases the risk x5
Describe the evidence that cigarette smoking (actively and passively) induces cancer.
1) In comparison with a non-smoker, a smoker is subject to a 1 : 22 increase in lung cancer risk
2) Appears to be a dose-response relationship between cigarette consumption and relative risk of developing lung cancer (smoking 10 cigarettes a day increases the risk x10 compared to non-smoker)
3) Positive correlation between increase in cigarettes smoked per head per year and deaths from lung ca per 100,000 per year (both increase), in both men and women (although women less evident due to social standards making smoking less acceptable in the mid 20th century)
4) Stopping smoking reduces risk (ex-smokers experience a decrease in the death rate from lung cancer, relative to current smokers, death rate becomes almost comparable to the risk of non-smokers after 20 years)
5) Tobacco smoke metabolites (e.g. cotinine which is a nicotine metabolite, and benzopyrene-albumin adduct) in plasma of young children higher when mother is a smoker (followed by when other relative is a smoker, usually father) than when there are no smokers in the family
Identify a specific type of lung cancer associated with smoking.
Squamous cell carcinoma of the lung