Flashcards in Carcinogenesis Deck (55):
What are the 4 major categories of carcinogen?
List the stages of chemical carcinogenesis (4 stages).
At what point does this chain of events become irreversible?
When the progression stage is reached and started
Briefly summarise initiation.
Mutagenic event which involves cellular genome mutation(s) in tumour supressor genes and/or proto-oncogenes
Briefly summarise promotion.
A reversible, non-mutagenic event which involves the stimulation of proliferation and causes both mutated and normal cells to proliferate
Briefly summarise progression.
Irreversible enhancement/repression of gene expression - the selection of neoplastic cells for optimal growth
What is malignancy?
Comment on the effect promotors have.
High dose of carcinogen = tumours develop
Low dose of carcinogen = no tumours develop
Low dose of carcinogen + promoter = tumours develop
Multiple doses of promotor = no tumours develop
What is a common cause of carcinogenesis associated with lifestyle?
Workers in the dye industry were common sufferers of carcinogenesis. What was the carcinogen present and what did it cause?
Describe the mechanism of action of 2-NPA.
Liver converts 2-napthylamine to its carcinogenic metabolite, 2-amino-napthol. This is then detoxified to glucoronide which isn't carcinogenic and is hence excreted to the kidneys. However, it then passes into the bladder (the normal pathway for excretion after leaving the kidneys) and is converted to a carcinogen due to the expression of the converting enzyme beta-glucoronidase by urothelial cells
What is asbestosis?
The formation of scar tissue in the lungs as a result of asbestos exposure
What medical condition can asbestosis lead to and by how much is the risk of this being brought about increased by?
Risk increased by factor of 5
Exposure to blue asbestos fibres carry an increased risk of what?
Mesothelioma (rare tumour with a 25-45 year latent period)
What three factors does risk of these conditions depend on?
What lifestyle choice can increase the chance of asbestos related tumour formation by 50 times?
What type of substance is asbestos?
Upon inhalation of needle-like asbestos fibres, what happens to them?
They become coated in proteins to become asbestos bodies
The formation of these asbestos bodies triggers an immune response; what type of leukocyte is primarily stimulated?
Monocytes ---> Macrophages
What is the published increase in risk of lung cancer associated with smoking?
22x more likely
How many chemicals are there in tobacco smoke?
What is the main active carcinogen present in tobacco smoke?
The polycyclic aromatic hydrocarbon: 3,4 BENZAPYRENE
What carcinogenic effect does 3,4 benzopyrene have?
GUANINE MUTATIONS IN K-Ras & p53 GENES
G-C PAIR IS REPLACED BY A-T PAIR
What is the role of GSTM1 (glutathione S transferase)?
Is the GSTM1 enzyme present in everyone?
The majority of people, but some individuals have a null genotype so no GSTM protein is detectable (30-50% of global population)
What does having a homologous null genotype increase the risk of?
Lung cancer along with mouth, bladder and kidney cancers
What type of chemotherapeutic agent can cause secondary carcinogenesis following cancer treatment?
What facilitates the conversion of 3,4 benzopyrene into benzopyrene idol epoxide (which has the damaging effect on DNA)?
Aryl Hydrocarbon Hydroxylase (AHH) (which is unregulated in smokers)
Where is a transitional cell carcinoma most frequently seen and where can it be expressed other than this site?
Anywhere where there are urothelial cells present
Increased risk of lung cancer associated with smoking is between what percentages?
15% - 24%
What is sidestream smoke?
Smoke that passes into the surrounding air rather than into the smokers' lungs
How can secondary tumours be brought about following use of alkylating agents in cancer chemotherapy
DNA damage to surviving normal somatic cells during treatment
This can lead to DNA strand breakage and base damage
Describe how nitrosamines (type of carcinogen) can enter the body.
Food additives or fertilisers that enter drinking water are ingested
GI bacteria convert the excess of nitrites and nitrates present into nitrosamines
What can nitrosamines cause?
Cancers of GI tract
Cancers of the liver
Which organ do poisoning aflatoxins target?
What can aflatoxins cause?
What two fungi are aflatoxins produced by?
Describe how aflatoxins can contaminate food, bearing in mind that they are of fungal origin.
At high temperatures and high levels of humidity, moulds develop on various NUTS (especially peanuts), seeds, on cooked and stored rice and on cereals
These moulds penetrate the cells of peanuts and secrete aflatoxins that contaminate the once edible nut
Aflatoxins and what other infection together predispose to over cancer?
Hepatitis B infection
What type of aflatoxin is a potent carcinogen?
What type of gene is p53?
TUMOUR SUPRESSOR GENE
Which type of GI tumour is more common; Small intestine or Large intestine?
Why is this type of GI tumour so much more common?
Bcl2 (a GROWTH PROMOTING GENE and hence prevents cell death/apoptosis) INCREASED EXPRESSION IN LARGE INTESTINE, thus promoting cell survival and as mutations accumulate, carcinogenesis occurs
Is Bcl2 expressed in the small intestine
Where is Bcl2 expressed specifically?
Crypts of clonic epithelium
Bcl2 over-expression seen in other cancers such as lung cancer is due to what?
What does a Bcl2 knock-out mean?
Basically moving Bcl2 and silencing its effects (so in large intestine, %age of apoptotic cells decreases vastly)
What two effects does UV radiation have on DNA?
Causes formation of pyrimidine dimers
Causes breakage of DNA via indirect mechanisms
Is UV radiation ionising?
What is the disease that means individuals are repair deficient to UV radiation?
Xeroderma pigmentosum (rare autosomal recessive disease)
What enzyme is deficient in xeroderma pigmentosum and what is the normal function of this enzyme?
Endonuclease - enzyme in the pathway of thymine dimer removal, hence repair of damage is defective
What are the symptoms and signs of xeroderma pigmentosum?
Severe skin abnormalities - freckling, multiple squamous and basal cell carcinomas and melanomas
What type of cancer did radium dial painters commonly contract and why were they so susceptible to it?
Radiation-induced bone cancer
They licked paint brushes carrying large amounts of radium salts and so ingested large amounts of radioactivity
How does radium get into the bone in the first place?
It follows calcium into the bone during calcium turnover