Carcinogenesis

Question 1

Identify the major categories of carcinogens.

Answer 1

1. Chemicals (e.g. smoking)
2. Radiation (e.g. UV, ionizing radiation)
3. Some parasites and Fungal toxins (e.g. aflatoxin)
4. Viruses

Question 2

Describe the mechanism of chemical carcinogenesis.

Answer 2

1. 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.
2. 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.
3. Progression: irreversible enhancement/ repression of gene expression. Selection of neoplastic cells for optimal growth genotype/ phenotype in response to the cellular environment
4. Malignancy/ Cancer

Question 3

Give an example of carcinogen and promoter.

Answer 3

Carcinogen:
-Methyl- cholanthrene

Promoter (accelerator)

• TPA (phorbol esters, present in Croton Oil)
• Dioxin (polycyclic aromatic compounds).

Question 4

Discuss the impact on different doses of carcinogen and promoter on carcinogenesis.

Answer 4

• 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

Question 5

Define carcinogen.

Answer 5

a substance capable of causing cancer in living tissue.

Question 6

Define initiator.

Answer 6

Substances that cause the initial changes or mutations in DNA (e.g. mutagens)

Question 7

Define promoter.

Answer 7

Type of epigenetic carcinogen that promotes neoplastic growth only after initiation by another substance.

Question 8

Define latent period.

Answer 8

Time between initiation and promotion event(/appearance of cancer)

Question 9

What is the result of a short vs long latent period ?

Answer 9

No effect on frequency of tumour in population, affects rate at which tumor develops (shorter latent period = tumor develops more quickly)

Question 10

Link the following with the tumour they induce and state where they may be found.

• Asbestos
• UVB
• Ionising radiation
• Aflatoxin
• Naphthylamine
• Benzpyrene

Answer 10

• 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)

Question 11

Outline the mechanisms of cancer induction in the bladder by napthylamine.

Answer 11

• 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

Question 12

Describe the relationship between years after start of exposure to carcinogen and percentage with bladder cancer.

Answer 12

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

Question 13

Describe results of asbestos exposure.

Answer 13

• 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

Question 14

Describe the evidence that cigarette smoking (actively and passively) induces cancer.

Answer 14

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

Question 15

Identify a specific type of lung cancer associated with smoking.

Answer 15

Squamous cell carcinoma of the lung

Question 16

Explain how, pathologically, Benzopyrene leads to lung cancer.

Answer 16

• 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

Question 17

Describe the process of detoxification of carcinogens.

Answer 17

• Glutathione S transferase (GSTM1) detoxifies carcinogens
• Some individuals have null genotype so no GSTM1 protein is detectable
• GSTM1 is polymorphic in the population, being null in about 30-50% of individuals depending on the ethnic group from which they come
• Homozygous null individuals have an increased risk of lung cancer and smoking-induced bladder cancer

Question 18

What cancers does smoking increase the risk of ?

Answer 18

• Lung cancers
• Oesophagus
• Bladder
• Kidney
• Pancreas
• Mouth

Question 19

Describe the features of bladder cancer as a result of cigarette smoking.

Answer 19

• Hematuria
• Transitional cell carcinoma
• TCC is often multifocal and has a tendency to recur.

Question 20

Where may Transitional cell carcinoma arise ?

Answer 20

Anywhere in the urothelium, but is most common in bladder.

Question 21

Describe the relation between passive smoking and cancer risk.

Answer 21

• Increased risk of lung cancer

- Estimates of increased risk vary between 15% and 24%

Question 22

What is the proportion of smoke in a room due to sidestream smoke ?

Answer 22

Nearly 85% of the smoke in a room results from sidestream smoke

Question 23

Why is sidestream smoke bad ?

Answer 23

Sidestream smoke is bad because many potentially toxic gases are present in higher concentrations in sidestream smoke than in mainstream smoke)

Question 24

Identify a major risk of chemotherapy.

Answer 24

• Although rare, secondary carcinogenesis can occur from the use of alkylating agents in chemotherapy
• Risk of secondary tumours following cancer treatment
• These result from DNA-damage inflicted on surviving normal somatic cells during treatment
• DNA strand-breakage and base damage induced

Question 25

Discuss the risks from carcinogens in the diet.

Answer 25

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

Question 26

Is liver cancer more common in Europe or Asia ?

Answer 26

Liver cancer commoner in Asia versus Europe

Question 27

Describe difference in incidence of cancer between the small and large intestine, and explain molecular basis for it.

Answer 27

-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

Question 28

What is the effect of knocking out gene responsible for Bcl2, on cancers of the large intestine and small intestine ?

Answer 28

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)

Question 29

Describe UV radiation and the cancers it gives rise to.

Answer 29

* 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 XP 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

Question 30

Describe the cancers given rise to by radiation.

Answer 30

SKIN CANCER • Common amongst early radiologists before the risks were appreciated since X-ray sources were used with total lack (necroses also common) LEUKAEMIA • Latent period is age dependent (smaller latent period with higher risk for younger patients, longer latent period with lower risk for older patients) BONE CANCER • Radium-dial painters licked paint brushes carrying radium salts and so injested large amounts of radioactivity • Radium follows calcium into bone during calcium turnover (diffuse distribution through bone) THYROID CANCER (e.g. Thyroid Carcinoma) • E.g. in Chernobyl • Radioactive Iodine uptake into thyroid gland can be detected by gamma-ray emission • Particularly in young children

Question 31

Identify some causes of cancer, ranking them from least controllable to most controllable.

Answer 31

``` Inherited Genes Radiation Infections UV Alcohol/Diet and weight and activity/Tobacco ```