20. Carcinogenesis - causes of cancer Flashcards
Give some examples of occupational carcinogens
- cadmium and nickel
- radon (mining)
- solvents and preservatives (painters and furniture makers)
- tannins (leather footwear manufacture)
Give examples of chemical carcinogens
- PAHs
- nitrosamines
Give examples of infectious agents as carcinogens
- HPV
- H. pylori
Give examples of radiation as a carcinogen
- UV light
- radon
Give examples of mineral carcinogens
- asbestos
- heavy metals
Give examples of physiological carcinogens
- oestrogen
- androgens
What are the carcinogens involved in chronic inflammation?
- free radicals
- growth factors
There is a very wide variety of agents implicated in carcinogenesis. What do they all have in common?
Prolonged exposure to each of these agents can lead to the accumulation of genetic alterations in clonal populations of cells
Which organ does aflatoxin target?
Liver
Which organs does alcohol target?
Pharynx, larynx, oesophagus, liver
Which organ does asbestos target?
Lung pleura
Which organ do X-rays target?
Bone marrow (leukaemia)
Which organ does UV light target?
The skin
Which organ does oestrogen target?
Breast
Which organs does tobacco smoke target?
Mouth, lung, oesophagus, pancreas, kidney, bladder etc
Which organ does HBV (hepatitis B virus) target?
Liver
Which organ does HPV (human papilloma virus) target?
Cervix
Carcinogen can also by non-genotoxic. What does this mean?
Induce proliferation and DNA replication
What is an INITIATOR?
A carcinogen that can modify or damage DNA (genotoxic)
What is a PROMOTER
A carcinogen that can induce proliferation and DNA replication (non-genotoxic)
What is a “complete” carcinogen?
A carcinogen that can both initiate and promote. eg. UV light
What does mutation induction (initiation) require?
- chemical modification of DNA
- replication of modified DNA and mis-incorporation by DNA polymerase
DNA polymerases make mistakes at a very low but significant rate. What does this result in?
Accumulation of genetic variation or polymorphisms in coding and non-coding sequences in the genome. Some of these changes are deleterious (mutations)
How might chemical modification of the nucleotides involved in base-pairing occur?
Through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes
Agents that are good promoters contribute to carcinogenesis in 2 important ways. What are they?
- stimulate the 2 rounds of DNA replication required for mutation fixation
- stimulate clonal expansion of mutated cells, which enables the accumulation of further mutations
Give an example to explain the stages of initiation, promotion and progression
- mouse skin tumour model
- genotoxic initiating agent damages DNA
- promoting agents fixes damage as a mutation and converts normal cell into mutated initiated cell
- promoting agent stimulates clonal expansion of initiated cell to produce papillomas
- further rounds of mutations and clonal expansion allows papilloma to progress to carcinoma
What makes DNA replication a more error-prone process?
DNA damage
DNA replication in the presence of DNA damage is an error-prone process that can result in permanent changes in DNA sequence
Repeated treatment with promoting agents/ exposure to exogenous or endogenous mutagens can result in what?
Gradual accumulation of mutations
Exogenous mutagens are environmental and endogenous mutagens occur naturally within cells. Give examples of the latter
- oxygen radicals
- lipid metabolism byproducts
Give some common genetic abnormalities
- base pair substitution
- frameshift
- deletion
- gene amplification
- chromosomal translocation
- chromosomal inversion
- aneuploidy
What is a base pair substitution also known as?
Point mutation
Explain base pair substitutions/point mutations
- smallest change in DNA sequence that can give rise to change in gene function
- can result in amino acid substitution (missense)
- or can introduce stop codon resulting in truncated protein product
What is a frameshift mutation?
Gain or loss of one to several base pairs that results in a shift in the reading frame of a gene transcript
What can gene amplification result in?
A cell having anything up to a hundred copies of a gene that it would normally only have two copies of
How can we illustrate that some chromosomes are present in appropriate numbers/exchange of material?
By chromosomal painting
Chr 9:22 exchange is a specific translocation. What is it known as and what is it associated with?
Philadelphia chromosome
Associated with chronic myeloid leukaemia
Chromosomal translocations can result in what?
- genes being moved to a more transcriptionally active region of the chromosome
- genes being recombined into new gene fusions
What is aneuploidy?
Any departure from the normal structure or number of chromosomes
How many cancer genes have been found with translocations?
about 300 of the 500 cancer genes
What causes epigenetic inactivation of TSGs? (most commonly)
Abherrent methylation of gene promoters (happens in in tumours)
Mutations found in oncogenes lead to what?
Mutations found in TSGs lead to what?
Mutations found in oncogenes lead to a gain in function
Mutations found in TSGs lead to a loss of function
What are direct acting carcinogens?
Interact directly with DNA eg. oxygen radicals, nitrosamines, UV light, ionising radiation
What are procarcinogens?
Require enzymatic (metabolic) activation before they react with DNA eg. aromatic amines, polycyclic aromatic hydrocarbons (PAHs)
Are the majority of carcinogens that we ingest direct acting or procarcinogens?
The majority are pro carcinogens and require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals
The majority of carcinogens that we ingest require metabolic activation by enzymes that normally detoxify and excrete toxic chemicals. In what way does thin introduce a genetic influence to our sensitivity to cancer?
People who activate a particular chemical more efficiently are more likely to get cancer
But those who excrete the activated chemical less efficiently are also more likely to get cancer
What are the products in the metabolic activation of benzopyrene?
Benzo pyrene
Benzo pyrene 7,8-epoxide
Benzo pyrene 7,8-dihydrodiol
Benzy pyrene 7,8-diol, 9,10-epoxide
Ultimate carcinogen = BPDE
What are the enzymes involved int he activation of benzopyrene?
P450 mixed function oxidases
Epoxide hydrolase
P450 mixed function oxidases
Give a classic example of a pro carcinogen and state how it can be generated
Benzopyrene
Can be generated through the combustion of most organic material such as meat, tobacco and fuel
BPDE causes mutation in which gene?
TP53
seen in this gene in the lung tumours of smokers
What are the 4 general stages in DNA damage and repair?
- Damaging agent
- DNA lesions
- Repair process
- Disease syndrome
Give a pathway from carcinogen exposure to cancer
- carcinogen exposure
- metabolic activation (eg. cytochrome P450s)
- DNA damage
(- DNA repair) - DNA replication
- DNA mutation (eg. in proto-oncogene or tumour supressor gene)
- progression
- cancer
Rather than metabolic activation leading to DNA damage, what else may occur?
Detoxification
Excretion
(eg. glutathione S-transferase)
At which stages of the pathway from carcinogen exposure to cancer may genetic modulation occur?
- metabolic activation
- detoxification and excretion
- DNA repair
(may explain why exposure does not always lead to cancer)
Give some defences against carcinogenesis
- dietary antioxidants
- detoxification mechanisms
- DNA repair enzymes
- apoptotic response to unprepared genetic damage
- immune response to infection and abnormal cells
Which cancers is alcohol linked to?
Oral Oesophageal Pharynx Larynx Breast Bowel Liver (Pancreatic)
What is alcohol converted into that can cause DNA damage?
Acetaldehyde
Alcohol increases levels of which hormones?
Oestrogen and testosterone
Alcohol increases the uptake of what?
Carcinogenic chemicals into cells within the upper GI
Alcohol reduces levels of what?
Folate, needed for accurate DNA replication
Alcohol can kill what?
Surface epithelium leading to unscheduled proliferation
All of the strongest risk factors for breast cancer are associated with what?
Increased exposure to oestrogen - can both stimulate cell division and induce DNA damage
Breast cancer risk decreases 20% for what?
Risk decreases 20% for each year that menarche is delayed
What procedure leads to 90% decrease in risk of breast cancer?
Oopherectomy
removal of ovaries
What procedure reduces incidence of prostate cancer?
Orchidectomy
removal of a testis
Which types of chronic inflammation have an association with cancer?
- colitis
- hepatitis
- Barret’s oesophagus
- metaplasia
- gastritis
- gallstones
Inflammatory response results in a ‘double whammy’. What does this mean?
- DNA damage from release of free radicals by immune cells - initiation
- growth factor induced cell division to repair tissue damage - promotion
Which cell is key in the link between inflammation and cancer?
Tumour-associated macrophages (TAMs)
What do TAMs release?
- TNFa
- ROS
- RNS
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are released by TAMS. What do they do?
They can act as complete carcinogens, resulting in mutation by damaging DNA and stimulating proliferation through induction of growth factors
ROS can also induce fibroblasts to undergo autophagy, which releases important nutrients that tumour cells can “feed” on
TNFa is also released by TAMs. Why does this do?
It is a cytokine that induces and maintains the inflammatory response
What are TAMS recruited by?
Recruited by cytokines released by tumour cells
