carcinogenesis

Question 1

define carcinogen

Answer 1

carcinogen - a substance capable of causing cancer in living tissue

Question 2

define initiator

Answer 2

initiator - substance which causes the initial mutation

Question 3

define promoter

Answer 3

promoter (accelerator) - substances which enhance the tumourigenecity after the initiator has caused a mutation

Question 4

define latent period

Answer 4

latent period - the gap between the initial exposure event to the carcinogen and the presentation of tumours

Question 5

carcinogens with the tumours they induce

Answer 5

carcinogen | tumour induced |
| — | — |
| asbestos | bronchogenic carcinomas/mesothelioma (chest cavity) |
| UVB | melanoma |
| ionising radiation | skin cancer/leukaemia/bone cancer/thyroid cancer |
| aflatoxin | liver cancer |
| naphthylamine | bladder |
| benzpyrene | lung cancer |

Question 6

major categories of carcinogens:

Answer 6

1. chemicals e.g smoking
2. radiation e.g UV, ionizing radiation
3. some parasites, fungal toxins e.g aflaxatoxin
4. viruses

Question 7

chemical carcinogenesis:

1. what is the carcinogen?
2. what is the promoter?

what are the multi-steps process?

Answer 7

chemical carcinogenesis
1. carcinogen = methyl-cholanethrene
2. promoter = croton oil - TPA

1. initiation
2. promoter
3. progression (irreversible)

Question 8

describe the multi-step process of chemical carcinogenesis?

Answer 8

1. initiation: Initiation (mutagenic) event involves cellular genome mutations in tumour suppressor genes and oncogenes
2. promoter: Promotion (reversible, not mutagenic) Stimulates proliferation and causes both mutated and normal cells to proliferate. e.g. TPA (phorbol esters), dioxin (polycyclic aromatic compounds)
3. progression (irreversible): irreversible enhancement/ repression of gene expression. Selection of neoplastic cells for optimal growth genotype/ phenotype in response to the cellular environment

Question 9

order of carcinogenesis:

Answer 9

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 of carcinogen + promoter = tumours develop

Question 10

when is the latent period longer?

Answer 10

latent period is longer when the onset of promoters is later after initial dose of carcinogen

Question 11

chemical carcinogenesis of the bladder:

what causes chemical carcinogenesis of the bladder?

what is the mechanism of processing in the body?

what does the latent period of onset and risk of bladder cancer depend on?

Answer 11

2-napthylamine used in the dye industry

• it is toxic due to the way its processed in the body:

mechanism
1. aromatic amines such as 3-naphthylamine are pre-carcinogens requiring activation
2. it enters the liver, which converts 2NTA to carcinogenic metabolite-2-amino-naphthal
3. metabolite 2-naphthal is detoxified to glucuronide which is extreted by kidneys and enters the bladder
4. in the bladder, human urothelial cells express beta-glucuronidase
5. the bladder converts glucoronide to a carcinogen (o-aminophenol)

the latent period of onset and risk of bladder cancer depends on the length of carcinogen exposure

Question 12

chemical carcinogenesis of the lung:

what causes bronchogenic carcinomas?
what causes mesothelioma?
what does risk depend on?

what is the mechanism of processing in the body?

Answer 12

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

mechanism
1. abestos is fibrous silicate substance which can be inhaled
2. when inhaled, the needle-like fibres become coated in proteins forming asbestos bodies
3. the presence of asbestos bodies excites a macrophage and gaint cell response, rather like silicosis

Question 13

chemical carcinogenesis of the lung: smoking and cancer

what causes cancer of smoking-induced lung cancer?

what are 2 genes most frequently mutated in smoking-related lung cancers?

what is the mechanism of processing in the body?

Answer 13

• benzoprene 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 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

mechanism
1. The active carcinogen in tobacco smoke is the polycyclic aromatic
hydrocarbon 3,4-benzpyrene (benz[a]pyrene)
2. This polycyclic aromatic hydrocarbon is converted by Aryl Hydrocarbon Hydroxylase (AHH*) into:
3. Benzo[a]pyrene diol epoxide that binds to DNA forming damaging products

*AHH is upregulated in smokers

Question 14

detoxification of carcinogens:

1. what chemical detoxifies carcinogens?
2. what do some individuals have?
3. what do homozygous null individuals have an increased risk of?
4. why do some smokers don’t develop lung cancer?

Answer 14

• 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 15

describe chemical carcinogenesis following chemotherapy

Answer 15

• 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 16

risk of carcinogens in diet:

how do nitrites and nitrates cause cancer?

Answer 16

nitrites and nitrates:

pathway for conversion of dietary nitrites and nitrates to carcinogens

Question 17

risk of carcinogens in diet:

how do food additives cause cancer?

Answer 17

food additives

fertilisers that enter drinking water

gut bacteria converts nitrites and nitrates into:

nitrosamines - which are carcinogens that can lead to cancers of gastro-intestinal tract and liver

Question 18

risk of carcinogens in diet:

what is aflatoxicosis?

what are aflatoxins?

what are examples of aflatoxins?

Answer 18

• 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 19

what is aflatoxin B1?

what may influence the rate of carcinogenesis?

Answer 19

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

• Carcinoma of the liver can result from heavy or prolonged exposure
• expression of genes in different regions of GI tract may influence rate of carcinogenesis

Question 20

what does Bcl2 protein do?

where is Bcl2 expressed?

how does Bcl2 lead to carcinogenesis?

why do less tumours arise in the small intestine?

where is Bcl2 overexpression seen?

Answer 20

Bcl2 increased expression suppresses apoptosis and increases cell survival

• Bcl2 is expressed in colonic epithelium, especially in the crypts
• In colon (large intestine) 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 and so less GI tumours arise in the small intestine
• Bcl2 overexpression by gene amplification is seen in some cancers e.g. lung cancer

Question 21

UV-light carcinogenesis:

what does UV radiation cause?

what does it form?

what are caucasions susceptible to?

usually UV damage is repaired, except in repair deficient individuals - what 3 groups of people are repair deficient?

Answer 21

UV radiation is non-ionising so causes the excitation of atoms and DNA damage

it forms pyrimidine dimers but can also break DNA by indirect mechanisms

caucasians are susceptible to melanoma and basal cell carcinoma

1. ppl with xeroderma pigmentosum - a rare autosomal recessive disease
2. Inherited deficiency of endonuclease, an enzyme in pathway of thymine dimer removal. Hence repair of damage is defective
3. Children who show severe skin abnormalities – freckling of skin, multiple squamous and basal cell carcinomas, and melanomas

Question 22

radiation carcinogenesis:

what cancers form due to radiation?

Answer 22

• necrosis and skin cancers
• radiation-induced leukaemia, with the latent period being age dependent
• radiation-induced bone cancer, seen in the radium-dial painters
• radiation-induced childhood thyroid cancer in children after chernobyl