Carcinogenesis

Question 1

What are some of the major carcinogens?

Answer 1

Chemicals (Smoking)
Radiation (UV, ionising, etc)
Some parasites, fungal toxins (aflatoxin)
Viruses

Question 2

What are the stages of the mechanism of chemical carcinogenesis?

Answer 2

Initiation

Promotion (reversible)

Progression (irreversible)

Malignancy

Question 3

Describe the mechanism of chemical carcinogenesis

Answer 3

Normal Tissue 
I
V
Initiation
I
V
Altered genotype of an ‘initiated’ cell
I
V
Promotion (reversible) 
I - Promotor (accelerator)
V
New phenotype emerges resulting in
clonal expansion of initiated cell (pre-neoplastic focal lesion)
I
V
Progression (irreversible)
I
V
Malignancy;
Malignant metastases (Neoplasia)

Question 4

What does the initiation event in chemical carcinogenesis involve?

Answer 4

Initiation (mutagenic) event involves cellular genome mutations in tumour suppressor genes and oncogenes

Question 5

What does the promotion (reversible) event in chemical carcinogenesis involve?

Answer 5

Promotion (reversible, not mutagenic) Stimulates proliferation and causes both mutated and normal cells to proliferate. e.g. TPA (phorbol esters), dioxin (polycyclic aromatic compounds)

Question 6

What does the progression (irreversible) event in chemical carcinogenesis involve?

Answer 6

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

Question 7

Describe some multi stage processes that would and would not induce carcinogenesis

Answer 7

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 8

Describe the mechanism of chemical carcinogenesis of the bladder by 2-naphthylamine?

Answer 8

Aromatic amines such as 2-naphthylamine are pre-carcinogens requiring activation
I
V
Liver
I
V
Converts 2NTA to carcinogenic metabolite 2-amino-naphthol
I
V
Detoxified to glucuronide (not carcinogenic)
I
V
Excreted by kidneys
I
V
Bladder - Human urothelial cells express b-glucuronidase
I
V
Converts glucuronide to a carcinogen

Question 9

What does latent period of onset AND risk of bladder cancer depend on?

Answer 9

Length of carcinogen exposure

Question 10

Discuss carcinogenesis from asbestos exposure

Answer 10

Asbestosis (formation of scar tissue in the lung as a result of exposure) more commonly predisposes to bronchogenic carcinomas, increasing the risk by a factor of five

However, exposure to ‘blue’ asbestos fibres carries a risk of Mesothelioma

Mesothelioma is a rare tumour that has a 25 – 45 year latent period

Risk depends on the duration and intensity of exposure

Risk of asbestos-related cancer is higher (1:50) in smokers as compared with non-smokers exposed to asbestos

Asbestos fibres
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

Question 11

Discuss mesothelioma from asbestos exposure?

Answer 11

Metastatic spread is uncommon

Mesothelioma is a bulky tumour that can fill the chest cavity

Question 12

How does smoking cause cancer?

Answer 12

Hooo boy

Benzopyrene Leads to Guanine Mutations in K-Ras and p53 in the Regions Found to be Mutated in Smoking-Induced Lung Cancers

K-Ras and p53 are the two genes most frequently mutated in smoking- related lung cancers

The active carcinogen in tobacco smoke is the polycyclic aromatic hydrocarbon 3,4-benzpyrene (benzo[a]pyrene)

This polycyclic aromatic hydrocarbon is converted by Aryl Hydrocarbon Hydroxylase (AHH) into:
Benzo[a]pyrene diol epoxide that binds to DNA forming damaging adducts
(AHH is unregulated in smokers)

Question 13

What part of the body detoxifies smoking carcinogens?

Answer 13

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
• Not all heavy smokers develop lung cancer. In these smokers AHH may not be expressed – DNA-binding epoxides are therefore not generated

Question 14

Other than lung cancers, what cancers are smokers at risk of?

Answer 14

Many, including oesophagus, bladder, kidney and pancreas

Question 15

Discuss the presentation of transitional cell carcinoma in smokers

Answer 15

transitional cell carcinoma (TCC) i.e.arising in the cell
Layer lining the bladder
TCC can arise anywhere in the urothelium, but is most common in bladder.
TCC is often multifocal and has a tendency to recur.

Question 16

Throw out some stats on passive smoking and cancer risk

Answer 16

Estimates of increased risk of lung cancer vary between 15% and 24%. Second-hand smoke causes an estimated 11,000 or more deaths in the UK each year.

Many potentially toxic gases are present in higher concentrations
in sidestream smoke than in mainstream smoke and nearly 85% of the smoke in a room results from sidestream smoke.

Question 17

What law passed on 5th December 2016 to protect children from second hand smoke?

Answer 17

A ban on smoking in a vehicle with anyone under the age of 18

Question 18

Discuss chemical carcinogenesis following chemotherapy

Answer 18

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 19

Discuss the main risks of carcinogens in diet from nitrites and nitrates

Answer 19

Pathway for conversion of dietary nitrites and nitrates to carcinogens:

Food additives
Fertilisers that enter drinking water
I
V
Gut bacteria convert nitrites and nitrates
I
V
Nitrosamines – carcinogens that can lead to cancers of gastro-intestinal tract and liver

Question 20

Discuss the main risks of carcinogens in diet due to aflatoxicosis

Answer 20

Aflatoxicosis is poisoning, especially of the liver
that results from ingestion of aflatoxins from contaminated food.

The aflatoxins are a group of structurally related
toxic compounds produced by certain strains of the fungi Aspergillus flavus and A. parasiticus

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

Question 21

Discuss carcinogenesis due to Alfatoxin B1

Answer 21

Aflatoxin B1 is a potent carcinogen in both human and animal species

Carcinoma of the liver can result from heavy or prolonged exposure Liver cancer commoner in Asia versus Europe

One of the most important accounts of aflatoxicosis in humans occurred in more than 150 villages in adjacent districts of two neighboring states in northwest India in the autumn of 1974

According to one report of this outbreak, 397 people were affected and 108 people died

A combination of aflatoxins and hepatitis B infection predisposes to liver cancer

Question 22

Discuss the risk from carcinogens in diet in the GI tract?

Answer 22

Expression of genes in different regions of GI tract may influence rate of carcinogenesis
Incidence of GI tumours in the UK
Small intestine 366 per year Large intestine 28,587 per year

Question 23

Why is there such a difference in yearly cases of GI tumours between the large and small intestines?

Answer 23

Bcl2 increased expression suppresses apoptosis and so increases cell survival

Bcl2 is expressed in colonic epithelium, especially in the crypts

In colon bcl2 protects damaged cells from dying

Thus, cells survive and accumulate mutations, leading to carcinogenesis

Bcl2 is not expressed in the crypts of the small intestine

Bcl2 overexpression by gene amplification is seen in some cancers e.g. lung cancer

Question 24

Discuss UV radiation in relation to cancer

Answer 24

• 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
• In a recent study 11 subjects received 10 full-body tanning salon exposures over 2 weeks
• Pyrimidine dimers and p53 protein expression were detected in their epidermal keratinocytes

Question 25

Discuss UV damage

Answer 25

• UV-induced damage is normally repaired, or cells undergo apoptosis when repair is overwhelmed
• Repair deficient individuals are particularly at risk.
• Xeroderma pigmentosum - rare autosomal recessive disease
• Inherited deficiency of endonuclease, an enzyme in pathway of thymine dimer removal. Hence repair of damage is defective
• Children show severe skin abnormalities – freckling of skin,multiple squamous and basal cell carcinomas, and melanomas
• Require protection from sunlight - delays/prevents tumour formation

Question 26

Discuss radiation carcinogenesis

Answer 26

Radiation-induced skin cancer
• Necroses and skin cancers were common amongst early radiologists before the risks were appreciated
• X-ray sources were used with total lack of protection
Latent period is age dependent - at least in A-bomb survivors

Question 27

Where is a common site of radiation linked cancer?

Answer 27

The thyroid