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 (formation of scar tissue in the lung as a result of exposure) + 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
Explain how, pathologically, Benzopyrene leads to lung cancer.
- K-Ras and p53 are the two genes most frequently mutated in smoking- related lung cancers. If not corrected by the cell’s DNA repair mechanism, this guanine “adduct” is misread as a thymine by the DNA polymerase that copies chromosomes during replication. Ultimately, the original G-C base pair may be replaced by a T-A base pair (= transversion)
- Cells treated with Benzopyrene ( 3,4-benzopyrene, the polycyclic aromatic hydrocarbo which is the active carcinogen in tobacco smoke) show the same spectrum of G-T transversions as found in the K-Ras and p53 of smokers. These mutational “hot spots” map well to the guanine binding sites of the Benzopyrene derivative BaP epoxide
- Converted by Aryl Hydrocarbon Hydroxylase (AHH, which is upregulated in smokers) into: Benzo[a]pyrene diol epoxide that binds to DNA forming damaging adducts
- Not all heavy smokers develop lung cancer. In these smokers AHH may not be expressed – DNA-binding epoxides are therefore not generated
What cancers does smoking increase the risk of ?
- Lung cancers
- Oesophagus
- Bladder
- Kidney
- Pancreas
- Mouth
Describe the features of bladder cancer as a result of cigarette smoking.
- Hematuria
- Transitional cell carcinoma
- TCC is often multifocal and has a tendency to recur.
Describe the relation between passive smoking and cancer risk.
- Increased risk of lung cancer
- Estimates of increased risk vary between 15% and 24%
Discuss the risks from carcinogens in the diet.
1) NITRATES AND NITRITES
- These can be in food additives, in fertilisers that enter drinking water
- Gut bacteria converts these into carcinogens
- E.g. may be converted into nitrosamines (carcinogens that can lead to cancers of gastro-intestinal tract and liver)
2) AFLATOXINS (naturally occurring carcinogen)
-Group of structurally related toxic compounds produced by certain strains of the fungi Aspergillus flavus and A. parasiticus
-Ingestion of aflatoxins from contaminated foods causes Aflatoxicosis (poisoning, especially of the liver)
-Under certain conditions of temperature and humidity the moulds develop on various nuts (especially peanuts), seeds and on cooked and stored rice and other cereals.
These moulds are able to penetrate the shells of peanuts and secrete aflatoxins that contaminate the kernels
-Aflatoxin B1 is a potent carcinogen in both human and animal species
-Carcinoma of the liver can result from heavy or prolonged exposure to Aflatoxin B1 (may induce signature p53 mutations)
-A combination of aflatoxins and hepatitis B infection predisposes to liver cancer
Is liver cancer more common in Europe or Asia ?
Liver cancer commoner in Asia versus Europe
Describe difference in incidence of cancer between the small and large intestine, and explain molecular basis for it.
-Much higher incidence of cancers of large intestine than small intestine
- Because expression of genes in different regions of GI tract may influence rate of carcinogenesis
- Bcl2 is expressed in colonic epithelium, especially in the crypts
- Since bcl2 protects damaged cells from dying, cells survive and accumulate mutations, leading to carcinogenesis in the colon
- Bcl2 is not expressed in the crypts of the small intestine
What is the effect of knocking out gene responsible for Bcl2, on cancers of the large intestine and small intestine ?
LARGE INTESTINE
-Knocking out gene has large effect on apoptosis (increases it)
SMALL INTESTINE
-Knocking it out has no effect on apoptosis (keeps it relatively the same)
Describe UV radiation and the cancers it gives rise to.
- Non-ionising (causes excitation of atoms)
- Damage DNA:
- Form pyrimidine dimers but can also break DNA by indirect mechanisms. Pyrimidine dimers and p53 protein expression may be detected in epidermal keratinocytes.
- Repair deficient individuals are particularly at risk since UV-induced damage is usually repaired or cells undergo apoptosis (why is why Xeroderma pigmentosum patients are more vulnerable)
- Gives rise to many cancers:
-Caucasians susceptible to melanoma and basal cell carcinoma
-Also squamous cell carcinomas
- Xeroderma pigmentosum - rare autosomal recessive disease due to inherited deficiency of endonuclease, an enzyme in pathway of thymine dimer removal (repair of UV damage is defective).
- Children with XP show severe skin abnormalities – freckling of skin, multiple squamous and basal cell carcinomas, and melanomas.
- Protection from sunlight delays/prevents tumour formation
Identify some causes of cancer, ranking them from least controllable to most controllable.
Inherited Genes
Radiation
Infections
UV
Alcohol/Diet and weight and activity/Tobacco
What are asbestos fibres?
Mesothelioma from asbestos exposure
