31 - Environmental Basis of Cancer Flashcards
What to know
- the 2 classes of carcinogens (initiators and promoters)
- describe the action of a physical (UV), chemical (tobacco) and biological (hep B) carcinogen
- how the type of mutation in in the p52 gene can help identify the nature of the carcinogen
Carcinogen
Cancer causing agent
Complete Carcinogen
Any agent that on its own at a sufficient dose will cause cancer
EG of a complete carcinogen
Polycyclic Aromatic Hydrocarbons (soot in chimney sweeps) > SqCC (squamous cell carcinoma)
Treat a mouse with a very low dose of PAH (complete carcinogen) and follow it up with repeated doses of another carcinogen they undergo what
- initiator
- followed by repeated doses of promoter
- development of premalignant lesions (papillomas)
- a few spontaneous develop in SqCC
- there is a very specific relationship between the 2 types of carcinogens (initiators and promoters)
Just initiator
tumor
no
Multiple promoter
tumor
no
initiator single low dose (can’t cause anything by itself) followed by several doses of P
papillomas > then SOME SqCC
Strong synergy between the 2 agents
Multiple promotor followed by 1 dose of initiator
Nothing
Sequence of application of the 2 agents is important
Initiator, leave long gap then promoter
Tumours
Initiation seems to be an irreversible process
Initiators are…
Irreversible in their effect
Promoter spaced out beyond a certain time period
Tumours don’t develop
Promoters are…
Reversible signal
Initiators…
Environmental agents that target DNA, induce mutations and alter gene structure
Promoters…
Target proteins, so change intracellular signalling pathways and alter gene expression
Synergy between initiators and promoters
Initiators deliver potentially carcinogenic damage. Promoters selectively stimulate the growth of initiated cells
Example of a promoter
Phorbol Ester
What % of new cancers are skin cancers?
80% - due to UV light (carcinogen)
UVB and UVA wavelength
UVB: short
UVA: long (blue)
UVB and UVA penetrence
UVB - weak penetrence so is absorbed earlier (more energetic)
UVB has strong penetrence
UVB and UVA sunburn
UVA doesn’t often cause sunburn (weak)
uvB does cause sunBurn (STRONG)
UVB and UVA effect on cells
UVA - UVA is absorbed by molecules in the skin that then use the energy to make ROS (affects signalling pathways)
UVB - damage DNA (changes covalent bonds)
UVB and UVA class
UVA - weak complete carcinogen (more like a promoter)
UVB is a complete carcinogen
3 types of carcinoma caused by UV radiation as a complete carcinogen
- basal cell carcinoma
- squamous cell carcinoma
- melanoma (rare but affects young people so lots of life years lost)
How can the type of initiator be inferred in BCC and SqCC?
The type of initiator can be inferred by the type of mutation found. I.e. P53
What gene is frequently found mutated in cancers of sunlight exposed skin?
p53
How does p53 work in cancers due to skin exposure to
- C to T transitions especially in dipyridine sequences
- CC to TT tandem mutations rare in any other cancer
p53?
TSG - restrains abnormal growth
Often mutated in skin cancers
The types of mutations in P53 give an indication of what the carcinogen is
p53 mutations
C > T esp at dipyridimine sites
CC > TT (rare)
How do p53 mutations work
- UV light breaks the double bond in adjacent cytosines/pyrimidines and links them by a cyclobutane bond to form a cyclobutane ring
- if this isn’t repaired and the cell replicates then polymerase n guesses and buts 2 As opposite the joined C’s
- in the successive replication 2 Ts replace the 2 Cs
- this mutation is definitive for UV as a carcinogen
What happens after UV exposure
- UVB damages DNA
- cells die by apoptosis by p53
- if p53 is mutated (C>T) becomes a heterozygote with 1 damaged allele
- apoptosis not as efficient in subsequent burns in the heterozygote p53 cells
- relative survival and expansion of mutant cells
- with every subsequent UV exposure the mutant p53 expand/die less efficiently
- form actinic keratoses (dry patches of macroscopic dysplasia)
- next UV dose is then likely to cause the loss of the remaining p53 allele
- loses control (loss of apoptosis regulation) and becomes a malignant cell
UVA?
Doesn’t cause sunburn but acts as a promoter
homo/wild type p53
hetero
homo mutant
efficient apoptosis (peeling sunburn) reduced p53 mediated apoptosis expanding mutants loss of apop > malignant change
What is the most intensively studied carcinogen
tobacco
most important preventable casue of morbidity and mortality (30% of cancers and 90% of lung cancers)
CVD biggest killer from tobacco
How many carcinogens in tobacco
60
PAH especially
PAHS
- in any partially combusted plant material
What kind of mutation do PAHs tend to cause in the P53 gene
G>T
(C>T in skin cancer)
Also acts as a promoter as binds AhR
NNK? Nicotine DERIVED products
- Carcinogen
- G > A and binds BAR (adrenaline rececptor) and nAChR
Is nicotine a carcinogen
no but it can be transformed at high T into NNK (carcinogen)
Break down product
How does nicotine acts as a carcinogen
- tobacco is cured a bond in nicotine breaks and there is an addition to the N atom to form NNK
- the body recognises NNK as foreign and hydroxylates the alpha carbon it to solubilise and get rid of it
- spontaneously breaks down and methydiazohydorxide is released
- methyldiazohydroxide is very reactive
- methyl interacts with and binds guanine
- methylation of guanine
- G - T is now 6OmethylG - T
- if not repaired by MGMT becomes 6OmethylG -C
- A -T
What is the mutation with NNK
G > A
UVB is C>T PAH is G > T
MGMT?
methyl guanine dna methyl transferase
High amount of lung cancers with G>A mutation seen in people without this repair enzyme
Where else is the G>T mutation seen besides people who don’t smoke?
People who cook over smoking fire (PAH)
How does NNK also affect cell signalling
- binds AChR and BAR
- RAS (oncogene that drives cell signalling)
- altered transcriptional activity
- new active genes and altered cell phenotypes
- proliferation, reduced apoptosis, therapy resistance, MIGRATION
NNK
Nitrosaminoketone
2 carcinogens for HCC
- aldehydes (inflam > breakdown of lipids)
- fungal toxin (alfatoxins from Aspergillus flavus)
What toxin is a carcinogen for HCC
Alfatoxins from Aspergillus flavus
How does aflatoxins work
- alkylates the end G in AGG
- (AFB)G-C
- A replaces the C
- (AFB)G-A
- T -A
What is the promotor and what is the initiator
- initiator is aflatoxin by aspergillus flavus (AGG>AGT)
- promoter is HBV (hep B virus)
How does HBV act as a promoter
- cell death/necrosis
- chronic inflam
- regeneration/proliferation
- proliferation of cells before they repair
- DNA damage fixed
- proliferation allows outgrowth of mutated cells giving rise to transformed clones
How does HBV act as a promoter
- HBV makes X protein
- inhibits repair
- binds P53 and indirectly activates RAs protein contributing to outgrowth of abnormal cells
What is the most important endogenous complete carcinogen in our bodies?
CHRONIC INFLAMMATION
makes ROS > scramble DNA and make alkylaters out of lipids
Also produces ROS that affect signalling pathways
Cytokines act as inducers of epithelial proliferation (repair)
