What is cancer?
A group of diseases all sharing similar characteristics
What are the characteristics that all cancers share?
They are all abnormal, uncontrolled growths of cells. They all show inappropriate proliferation, invasion, and metastasis
What are the characteristics of a benign tumour?
- Slow growth
- No metastasis
What are the characteristics of a malignant tumour?
- Rapid growth
- Potential for metastasis
What is the increase in incidence of cancer due to?
- Lifestyle changes
- Increased screening
What is carciogenesis?
The process of transformation of a 'normal' cell to a cancer cell
What are the stages in carciogenesis?
What happens in initiation?
A mutation in stem cells is acquried when they are exposed to a carcinogen, and you get unrepaired DNA damage
What happens in promotion?
There is induction of cell division, where the cancer starts from a single cell that has a selective advantage over other cells within the same tissue
How does promotion lead to progression?
Increased proliferation means increased mutations and therefore an increased advantage
What happens in progression?
What is there a potential for in transformation?
What can be produced in cancer evolution?
A drug resistant clinical tumour
What happens in cancer metastasis?
Spread of transformed cells
What stages of carciogenesis can be used to treat cancer?
Can enter at any stage to try and prevent disease
What does mutation lead to in colorectal carciogenesis?
Inactivation of the APC gene
What will an inactivation of the APC gene in colorectal carcinogenesis cause?
May cause a change in frequency in division, which leads to an increase in stem cells. This will develop over time into a cluster of APC-less cells with stem cell properties
What might the 'second hit' be in colorectal carcinogenesis?
Inactivation of Ras
What is the result of the inactivation of Ras in colorectal carcinogenesis?
Increased selective advantage
What might the third hit be in colorectal carcinogenesis?
Inactivation of p53
What happens after the third hit in colorectal carcinogenesis?
Increased growth, starts to form an adenoma
What does the forth hit in colorectal carcinogenesis lead to?
The rapid development of cancer
What extracellular/environmental factors can cause genes to mutate?
- Binding of ultimate carcinogens
- Ionising radiation/UV
- DNA translocation
What do ultimate carcinogens do?
Bind to DNA and alter the sequence
What effect does ionising radiation and UV have on DNA?
Causes strand breaks and cross links
When may DNA translocation cause mutations?
When it is translocation to transcriptionally active regions
What intracellular factors can cause mutations?
- Misinterpretation of code
- Polymerase slippage/base misalignment
- Ineffective repair
What can all mutations potentially affect?
What can act as initiating stimuli in carcinogenesis?
- Chemical carcinogens
- Oncogenic viruses
- UV light
- Oxygen free radicals
- Replication errors
When can oxygen free radicals act as an initiating stimuli for carcinogenesis?
When there is an imbalance between their production (which happens naturally) and their removal
What are the categories of directly acting carcinogens?
- Alkylating and acylating agents
- Weak carcinogens
Give three examples of alkylating or acylating agents that can act as carcinogens
What can act as a weak carcinogen?
Give an example of a class of procarcinogens
Polycyclic aromatic hydrocarbons
When might polycyclic aromatic hydrocarbons be produced?
During the combusion of organic compounds, e.g coal, petrol, cooked foods, tobacco, smoke
What does exposure to polycyclic aromatic hydrocarbons typically cause tumours?
Lung and colon
Where is aflatoxin found?
In fungus found on peanuts and other foodstuffs
What are the steps in the metabolic toxification of aflatoxin?
Aflatoxin B1 + Mfo --> Aflatoxin-2,3-epoxide
Alfatoxin-2,3-epoxide is highly reactive, so will react with DNA to form a DNA adduct
What does exposure to aflatoxin correlate to?
The risk of liver cancer
Where is liver cancer related to aflatoxin prevalent?
In hot regions
How can you determine aflatoxin exposure?
- Can measure content in food
- Can measure DNA adduct
What happens to genes in cancer?
- Oncogenes are activated
- Tumour supressor genes are inactivated
What mutations can occur to a gene?
- Alteration of bases
- Strand break
- Base oxidation
- Deletion of bases
- Adducts of carcinogens and base
- Chromosomal translocation/rearrangement
- Gene amplification
Describe the severity of different DNA strand breaks?
If it's a single strand break, the body can normally repair it. Double strand breaks normally can't be repaired
How does an adduct mutation cause cancer?
A chemical binds to the base, and so repair mechanisms either can't get part that point on the DNA, or don't know what base to replicate
What mechanisms are in place to prevent mutations causing cancer?
- Repair mechanisms
- Mismatch and excision repair
What causes single point mutations?
What are the type of single point mutations?
What is a transition mutations?
- Purine -> purine (A -> G, G -> A)
- Pyrimidines -> pyrimidines (C -> T, T -> C)
What is a transversion mutation?
- Purine -> Pyramidine
- Pyramidine -> Purine
What causes structural chromosomal abberations?
What structural chromosomal aberrations can occur?
- Chromatid interchanges
What causes genome mutations?
What is aneuploidy?
An increase in the number of chromosomes in the cell
What is the most common nucleophilic binding site on DNA?
Is N7 on guanine highly mutagenic or not?
No, it is easily repaired
What is the guanine N7 commonly used for?
What guanine nucleophilic binding sites are highly mutagenic?
N2 and N3
How does mutagenesis by adduct formation occur?
- An adduct binds to the base
- After the first replication, the adduct is maintained in the sequence for one copy
- After replication of the copy with the adduct, you get a different amino acid, resulting in a different protein and therefore different structure
What proportion of base changes result in pernament mutation?
Fewer than 1:1000
What are the DNA repair pathways?
- Excision repair
- Error-prone repair
- Mismatch repair
- Defects in DNA replication
What can be removed in excision repair?
What enzymes perform base excision?
What does nucleotide excision remove?
Bases with bulky adducts
Is excision repair error prone or error free?
What is error-prone repair a response to?
Severe DNA damage
What happens in error-prone repair?
Low fidelity DNA polymerases recognise specific lesions, and restore the original sequence
Accepts error, but fixes gross changes
What is mismatch repair?
Proofreading by exonuclease part of DNA polymerase
How does repair occur in mismatch repair?
- Correcting mismatched bases in new strand during DNA replication
- Genetic recombination
How are defects in DNA replication used in repair?
- Genome rearrangements
- Chromosome loss
What things can act as promoting agents?
- Chemical promoters
- Microbial infection
Give 4 classes of chemical promoters
- Phorbol esters
Give three examples of where inflammation and infection can act as promoters
- Chronic irritation
- Bacterial infection
Give an example of an endoparasite that can act as a promoter
Give an example of a bacterial infection that can act as a promoter
What factors increase the risk of breast cancer?
- Older age at menopause
- Post-menopausal hysterectomy
- Oral contraceptives
- Younger age at menarche
What factors decrease the risk of breast cancer?
- More children
- Pre-menopausal hysterectomy
What factors increase the risk of getting cancer?
How can food act as carcinogens?
- Can contain carcinogens/mutagens
- Can contain toxins
- Calories can alter the hormone balance
- Inflammation/oxidative stress inducers
- Hot drinks/food can cause inflammation in mouth and oesophagus
What foods increase the risk of cancers?
- Red meat intake
- Animal fat
- Salted fish
- BBQ and chargrilled foods
- Salt-preserved foods
- Contaminated foods
What evidence is there for the link between certain foods and cancer?
- Migration studies
- Intervention trials
What are the components of the diet?
- Other compounds; procarcinogens, promoters, alcohol
What are the categories of macronutrients?
What are the categories of micronutrients?
What does red meat consumption increase the risk of?
What effect does cooking red meat have on its carcinogenic risk?
It increases the heterocyclic amine concentration by 50-100x. HA's are mutagenic.
What happens to heterocyclic amines in the liver?
They are metabolised to genotoxic metabolites
What has shown heterocyclic amines to be mutagenic?
What has shown heterocyclic amines to be carcinogenic?
In vivo models
What can increase the HA levels in food?
Increasing the cooking time
What can reduce the HA levels in food?
What are the sources of acrylamide?
- Used as drinking water clarifier
- Found in cigarette smoke
What is the problem with acrylamide?
It is a genotoxic metabolite, which adducts with DNA in vivo
However, the human evidence for cancer is scarce