Carcinogenesis Flashcards
State the major categories of carcinogens
Chemicals (smoking)
Radiation (e.g. UV, ionising radiation)
Viruses
Some parasites - fungal toxins (e.g. aflatoxin)
State the mechanism of chemical carcinogenesis
Initiation (by a carcinogen)
Promotion - (by an accelerator) [reversible]
Progression [irreversible]
Malignancy
Describe the mechanism of chemical carcinogenesis
Normal tissue
(addition of carcinogen)
Altered genotype of an ‘initiated’ cell
New phenotype emerges resulting in clonal expansion of initiated cell (pre-neoplastic focal lesion)
Malignant metastases (neoplasia)
What are promotors also known as ?
Accelerators
Carcinogen
A carcinogen is a substance, organism or agent capable of causing cancer
Initiator
Compounds capable of initiating tumour development may act directly to cause genetic damage.
OR
They may require metabolic conversion by an organism to become reactive.
Promoter
Tumor promoters are substances that enhance tumorigenicity when administered after a carcinogen.
Latent period
Time between initiation of exposure/ dose of carcinogen to the presentation of the tumours.
What does an initiation event involve ?
Initiation (mutagenic) event involves cellular genome mutations in tumour suppressor genes and oncogenes.
Promotion
Reversible, Not Mutagenic
What does promotion involve ?
Stimulates proliferation and causes both mutated and normal cells to proliferate.
e.g. TPA, dioxin
Progression
Irreversible enhancement
Repression of gene expression
What does progression involve ?
Selection of neoplastic cells for optimal growth of the genotype / phenotype in response to the cellular environment.
Feature of carcinogenesis
Multi-stage process
High dose of carcinogen
Tumours develop
(carcinogen acts as both initiator and promoter/accelerator)
Low dose of carcinogen
No tumours develop
Multiple doses of promoter
No tumours develop
Low dose of carcinogen + promoter
Tumours develop
Chemical carcinogenesis of the bladder
Bladder cancer - common in workers in the dye industry
Carcinogenic compound was: 2-napthylamine
Function of 2-napthylamine
Used as an intermediate in the manufacture of dyes and as an anti-oxidant in the rubber industry.
Carcinogenic compound in bladder cancer.
Describe 2-napthylamine
Aromatic compounds such as 2-napthylamine are PRE-CARCINOGENS requiring activation.
- Processed in different parts of the body
Action of the liver on 2-napthylamine
Convertes 2NTA to carcinogenic metabolite 2-amino-napthol
Detoxified to glucuronide
Excreted by the kidneys
Action of the bladder on 2-napthylamine
Glucoronide collects in the bladder
Human urothelial cells express Beta-glucuronidase
This converts glucoronide to a carcinogen (o-aminophenol)
What does the latent period of onset and risk of bladder cancer depend on ?
Length of carcinogen exposure.
Short onset (latent) –> high risk of cancer
Longer onset (latent) –> reduced risk of cancer
Asbestosis
Formation of scar tissue in the lung as a result of exposure.
Commonly pre-disposes to bronchogenic carcinomas, increasing the risk by a factor of 5.
Result of Asbestos exposure
Mesothelioma
Risk depends on the duration and intensity of exposure
Latent period of mesothelioma
25-45 year
Rare tumour - mesothelioma
Asbestos fibres
Asbestos is a fibrous silicate substance
When inhaled, the needle like fibres become coated in proteins and their presence excites a macrophage and giant cell response, rather like silicosis.
Features of Mesothelioma
What is the problem ?
Metastatic spread is uncommon
Problem is local spread, changes in the lung tissue, which destroys the lungs.
What is mesothelioma ?
A bulky tumour that can fill the chest cavity.
Statistic relating to cigarette smoking an cancer risk
IN comparison with a non-smoker, a smoker is subject to a 22 fold increase in lung cancer risk.
Stopping smoking reduces risk of cancer
Changes in DNA causing lung cancer to form - due to smoking
K-Ras and p53 are the 2 genes most frequently mutated in smoking-related lung cancers.
Causes of guanine mutations in K-Ras and p53
(3,4) Benz(o)pyrene
Binds to DNA leading to guanine mutations.
Active carcinogen in tobacco smoke
Polycyclic Aromatic Hydrocarbon 3,4-benzpyrene
This is converted by AHH into Benzopyrene diol that binds to DNA forming damaging adducts.
What is upregulated in smokers ?
AHH
What detoxifies carcinogens ?
Glutathione S transferase (GSTM1) detoxifies carcinogens.
Why may some heavy smokers not develop lung cancer ?
AHH may not be expressed
DNA binding epoxies are therefore not generated.
Cigarette smoking and cancer risk
IN addition to the risk of lung cancers, there is an increased risk of other cancers.
e.g. oesophagus, bladder, kidney and pancreas
TCC
Transitional cell carcinoma
Arises in the urothelium - bladder
Multifocal and has a tendency to recur.
Passive smoking and cancer risk
Increased risk of lung cancer
Most potentially toxic gases are present in higher concentrations in side stream smoke than in mainstream smoke.
Nearly 85% of smoke in a room results from side stream smoke.
Chemical carcinogenesis following chemotherapy
Secondary carcinogenesis can occur from the use of alkylating agents in chemotherapy.
What causes an increased risk of secondary tumours following cancer treatment ?
DNA damage inflicted on surviving normal somatic cells during treatment.
DNA strand-breakage and base damage induced.
Risk from carcinogens in diet
Risk involved with nitrites and nitrates
Food additives / Fertilisers that enter drinking water –>
Nitrosamines - carcinogens that can lead to cancers of gastro-intestinal tract and liver.
Aflatoxins
Naturally occurring carcinogens
- poisoning of the liver
- results in ingestion of aflatoxins from contaminated food
What produces aflatoxins ?
Fungi Aspergillus Flavus
A. parasiticus
What is a potent carcinogen in both human and animal species ?
Aflatoxin B1
Liver cancer
- p53 mutations in liver cancer
What predisposes to liver cancer ?
A combination of aflatoxins and hepatitis B infections.
Influence of rate of carcinogenesis
GI tract
Expression of genes in different regions of the GI tract.
Large intestine has a much larger incidence than in the small intestine.
Function of BcL2 expression
Increased BcL2 expression suppresses apoptosis, which increases cell survival.
BcL2 expressed in the large intestine.
BcL2 NOT expressed in the small intestine.
BcL2 expression in the large intestine function
BcL2 expressed in the crypts of the large intestine.
BcL2 protects damaged cells from dying.
Thus, these cells survive and accumulate mutations, leading to carcinogenesis.
What causes BcL2 over-expression ?
Gene Amplification
Effect of BcL2 knockout on small / large intestine
Small - No effect on apoptosis
Large - Large effect on apoptosis
UV-light carcinogenesis
Malignant Melanoma Incidence
UV radiation
Non-ionising (causes excitation of atoms)
Damage DNA
Form pyrimidine dimers but can also break DNA by indirect mechanisms.
Xeroderma pigmentosum
Rare autosomal recessive disease
Inherited deficiency of endonuclease - an enzyme in the pathway of thymine dimer removal.
Hence repair of damage is ineffective.
Radiation carcinogenesis
Radiation induced skin cancer
- Necroses and skin cancer most common amongst early radiologists
Latent period of radiation induced leukaemia
Latent period is age dependent
Higher age group, longer the latent period
Radiation induced bone cancer in radium dial patients
Radium follows calcium into the bone during calcium turnover.
Radium is radioactive.
Chernobyl radiation
Thyroid cancer in children after Chernobyl.
Controllable factors contributing to cancer
UV light
Alcohol
Diet/ Weight/ Activity
Tobacco
