Cancer 3 Flashcards
What factors support hte multi-hit model of carcinogenesis?
- Genetic homogeneity in cells from given tumour
- Cancer incidence increases with age
- In vivo evidence of cooperative effects of mutations to drive cancer
How does colorectal cancer support hte multihit model of carcinogenesis? (3 marks)
- Polyps arise in colon epithelium due to loss of tumour suppressor gene APC (encodes growth inhibiting protein)
- At this point polyp normally benign but can become cancerous - an adenoma - when mutations occur
- Can occur over 10-20 years
How does a polyp go from an adenoma to a malignant tumour?
(5 marks)
- Excessive epithelial proliferation = oncogene (Ras activated)
- Small tumour
- Large tumour (1/3 tumour suppressor genes lost - p53 gone)
- Tumour becomes invasive
- Metastasis
What is the difference between ‘driver’ mutations and ‘passenger’ mutations?
Driver mutations: occur in genes that’ll give a growth advantage
Passenger mutations: are silent and have no impact on gene product
What are ‘indogenous’ mutations?
Normal mistakes in DNA which can be repaired
Is inflammation an enabling characteristic?
Yes x
How does radiation affect DNA and cause cancer?
(4 marks)
- High radiation hits molecule, changes it from neutral to electrically charged
- Damages DNA directly due to radiolysis of water
- Radiolysis causes H2O2, hydroxy radical and superoxide radical to be generated
- H2O2 most dangerous as stays stable for longer to interact with DNA
What are risk factors increase experiencing gamma radiation? (3 marks)
- Exposure to X-rays
- Living at high altitude
- Plane travel
How does UV radiation lead to the misread of a DNA strand?
(3 marks)
- Double bonds in DNA absorb UV causing it to bend and kink
- Due to formation of pyrimidine dimer - specially cyclobutane
- Pyrimidine dimers are responsible for at least 80% of UVB induced mutations
- Normally have mechanism to trigger apoptosis in cell but those damaged by UVB avoid being killed by apoptosis
How do chemical carcinogens work? (2 marks)
HAve an electrophilic version of carcinogen which reacts with a nucleophilic site in purine and pyrimidine rings of nucleic acids
How do direct acting carcinogens work?
- Exist in highly readily active forms
- React with N+ and O2+ atoms in DNA
How do indirect acting carcinogens work? (4 marks)
- Exist in unreactive forms - water solube and can dissolve
- Get an electrophilic centre made by enzyme modifications by cytochrome P450 enzyme
- Converted via metabolism inot carcinogenic agent
- Interacts with DNA to form adducts and DNA becomes unstable
What is a DNA adduct?
Segemnt of DNA bound to cancer causing chemical
Where do aromatic amines come from ad how can they lead to cancer formation?
(4 marks)
- From cooked meats
- 2 amino acids converted by cytochrome P450
- This interacts with guanine to form huge adduct makes base unstable
- Base comes out of DNA and DNA is misread
What is the name of the carcinogen found in cigarette smoke?
Benzo[a]pyrene
Outline the process of lung cancer caused by benzo[a]pyrene.
(5 marks)
- Benzo[a]pyrene
- (encounter P450 enzyme CYP1A1 - exp in lung tissue)
- BP diol epoxides
- Forms adducts with purine bases
- G to T transversions
- Error prone DNA replication
- Could lead to lung cancer
What does neoplasm/plastic mean?
- Abnormal growth of cells
- Neoplastic diseases are any that cause tumour growth - benign or malignant
What is the virus causative of cervical cancer?
Human papillomavirus
- Produces a viral protein that blocks tumour suppressor actin.
- Done by protein-protein interactions
How can a retrovirus be tumour causing?
- Replicates and integrates its viral genome into host DNA and uses host cell machinery to make viral proteins
- Will mutate normal genes that have a dominant effect in the cell
How can bacteria be tumour causing?
- Can cause chronic inflammation that helps promote cancer
How does ROS contribute to cancer formation?
- Produced from oxidative respiration and lipid peroxidation (normal forms of metabolism)
- Breathing generates ROS intermediates
- In respiration O2- is made from reduction of NADH which makes less reactive superoxide radical
Give examples of endogenous reactions that may generate mutations and cause cancer.
- Pathogen killing by immune cells (by macrophages)
- Enzyme reactions
- Carcinogens from natural endogenous molecules being metabolised e.g. oestrogen - potent driver of cell proliferation
What is the most common chemical reaction that causes cancer?
Deamination of cytosine to uracil
