Environmental basis of cancer Flashcards
Human cancer
Skin cancer: most common
Lung cancer: most lethal
Hep B induced Liver cancer: 2nd major carcinogen effecting humans
Molecular Epidemiology
Links the environmental agents which induce the cancer
Relates enviro to cancer, via studying molecular changes
Complete Carcinogen
An agent which alone has the complete capacity to induce cancer
History of the Complete Carcinogen
1775 Percival Pott: High amount of SqCC (squamous cell carcinomas) in boys who went up chimneys
-specific type of skin cancer associated with chimney sweeps
-linked development of this cancer with soot exposure (component causing PAH (Polycyclic Aromatic Hydrocarbons))
PAH= very hydrophobic chicken wire molecules - benzene linked together
= complete carcinogens
If dilute can see synergy between 2x types of agents
Classical Carcinogenic model
Demonstrates synergy between 2x environmental components
Initiator and Promotor
Classical Carcinogenic model Mouse
- I = Initiator (PAH)
Single low (diluted) complete carcinogen
-diluted so much that cannot cause cancer itself - –Multiple doses of P Promotor (phobol esters from plants)
–synergises with promotor class of carcinogens –> - Papillomas
-benign tumours on skin
-most regress - Fully Malignant SqCC
-small number of papillomas the fully progress
Treatment and Cancer Scale
Initial low does of Initiator alone= mouse doesnt develop cancer
Multiple treatments of Promotor alone PPPP
But low dose I + PPPP = papillomas and SqCC appear
=strong evidence between 2x different types of environmental agents
Specificity about order: Initiator has to come first
Relative Duration: Initiator is Irreversible -delivers long term signal to cell. When acted upon much later by promotor can still induce tumours
Promotor effect Reversible : Multiple Promotors must be giving close to one another
Specificity, Duration and Reversibility of Initiator and Promotors
- Specificity about order: Initiator has to come first
- Relative Duration:
a) Initiator is Irreversible -delivers long term signal to cell. When acted upon much later by promotor can still induce tumours
- target DNA
b) Promotor effect Reversible : Multiple Promotors must be giving close to one another
Mechanism of Initiators
PAH (Polycylic Aromatic Hydrocarbons)
Initiators target DNA
I interact with DNA, causing DNA damage, causing mutation which are heritable by all future cells
=explains irreversibility of system
Mechanism of Promotors
(phobol esters from plants)
Promotors target proteins
-enzymes
-receptors
Proteins turn over (can effect a protein, leave for a while. Protein will be broken down and replaced by new protein)
= Reversibility of promotor effect
Promotion is applied continuously if wanting to add carcinogenic stimulus into system
Initiator summary
PAH Permanent duration DNA target 1. induces damage 2. heritable change Result: Mutations (due to changes to DNA) Changes Gene sequence Overall: Initiator mechanism induced potentially carcinogenic damage (pot. cancer causing)
Promotor Summary
Phobol esters (from plants)
Transient duration
Protein target
Signalling pathways altered
Changes Gene expression (same gene expressed in different ways changing the genetic environment of the cell)
Overall: Promotor mechanism selectively causes outgrowth of initiated cells
3x types of Skin cancer
- Basal cell carcinoma
- most common cancer of caucasians - SqCC
- Basal CC rel. more common - Melanoma
- SqCC more common
- hits and kills in younger people
Skin cancer carinogen
UV
- UVB and UVA
- exposed to it all the time
UVB
290-320nm shorter Wavelength Weakly penetrates into skin (good as is more energetic and would cause more damage) Powerful inducer of Sunburn Targets DNA (potent) Potent Complete Caricnogen
UVA
320-400nm longer Wavelength Stronger penetrating - can get down to basal layer Weak inducer of Sunburn Targets Substances in skin, loose energy and produce ROS (reactive O2 species) in skin -low ROS levels: change cell signalling -high ROS levels:mutagenic Weak complete Carcinogen Potent Promotor
Sunscreen
Have a sunscreen that absorbs both UVB and UVA
-if doesn’t absorb UVA think you’re safe, but can get large amount of UVA that can promote damage
Mutational spectrum re Skin cancer
smoking gun relating skin cancer to inducing agent
p53 gene
-tumour supressor gene
-signature mutation C–>T Base change at Dipyrimadine sites
-sometimes CC–>TT Tandem mutations (specific signature of UVB)
UV onto Skin (Initiator)
Potent initiator
1. Pyrmadine Dimer= Induce damage to adjacent pyrimadines
=between 2x C’s, 2x T’s, or C&T
=crosslinks adjacent bases
2. Hopefully can be repaired
3. If cell replicated,
a) DNA polymerase Eta. is error Error Prone. -emergency: Shoves in 2x AA (rush attempt to finish DNA replication)
b) other strand produce normal
4. Another round of replication
TT now opposite the Aa
Mechanism: accounts for DNA fingerprint assoc. with UV light induced damaged. Potent initiator that first damages, and then is next Mis-processed to produce mutation
Overall Initiator (UV) mechanism
Potent initiator that:
1. first damages DNA
2. then is next Mis-processed to produce mutation
Mechanism: accounts for DNA fingerprint assoc. with UV light induced damaged.
UV onto Skin (Promotor)
- UV light damages DNA
a) i) p53 (genome guardian) induced
ii) p53 induces Apoptosis to remove at risk cells
-peeling sunburn
-peeling sunburn isnt result of direct toxicity from UV
b) sometimes p53 gene itself is targeted by UV and one alleles mutated
i) -next sunlight damage
-p53 mutant clone will hang around better than wild type cells
- cells don’t apoptose as effectively
ii) with every cycle of damaging sun exposure, mutant clone wil expand relative to surrounding wild type fully apoptotic cells
iii) results in patches of Premalignant Actinic Keratoses when old:
-Actinic= sunlight induced
-Keratoses= patches of dry skin
=macroscopic collections of p53 Heterozygous (still normal w. p53 function, but less than there should be)
iv) another dose of sun on a sufficiently big target ==> produce p53 knockout/homozygous mutant
-loss of cell cycle control, DNA repair, apoptosis
-now actinic keratosis can become malignant B/SqCC
What patches of skin can you end up with when you’re older?
results in patches of Premalignant Actinic Keratoses when old:
-Actinic= sunlight induced
-Keratoses= patches of dry skin
=macroscopic collections of p53 Heterozygous (still normal w. p53 function, but less than there should be)
How is UV a promotor
Selects for cells which accumulate p53 mutation
What is the consequence of been savagely sunburnt as a child?
Likely will have Initiated cells in skin (p53 heterozygotes)
Every exposure to UVA= potential for outgrowth of mutant clone
-need sunlight and vit. C to be healthy
-but damaging sunlight can cause longterm outgrowth of cells that were mutated a long time ago
Old people skin
Patchwork of mutant clones
-shows you can tolerate a certain amount of mutations
Lung Cancer Carcinogen
Tobacco
-90% of lung cancers
-30% of all cancers
Cancer isnt the biggest source of mortality in smokes. CVD is larger
–> Lung cancer is Secondary Largest studied system:
-experimental organism: human
-end point: cancer development and death
Lung Cancer Subtypes
- Adenocarcinoma LC: 40%
- Bronchial epithelial, Surfactant secreting cells
- most likely for non-smokers - SqCC LC: 30%
- Bronchial (large airways) epithelial cells - Anaplastic LC: 10%
- poorly differentiated adenocarcinoma, SqCC
- cannot tell what they are as so badly differentiated - Small cell LC:20%
- Bronchial Endocrine cells
Cancer of non-smokers
Adenocarcinoma
-SqCC, Anaplastic and Small cell almost purely Tobacco induced
Tobacco Carcinogenic agents
60 known carcinogenic agents in Tobacco smoke
- PAH
- doesn’t matter what you smoke, if you breath in partially combusted Plant matter, it will contain PAH - NNK
- Nicotine derivatives (nitrocellular ketone)
- Nicotine itself is not a carcinogen. but when prepared/pyrosynthesis when lit up = breaks down into Nicotine derived Nitrocellular Ketone = Complete Carcingoen
Tobacco Carcinogens as a complete Carcinogen
Both act as both Initiators and Promotors
1. PAH(Benz alpha Pyrene)
Initiator: G–>T mutation
-DNA damage w large/bulky molecules
Promotor: binds to AhR (Aryl Hydrocarbon Receptor)
-changes gene expression
2. NNK
Initiator: G–>A mutation
-binds Beta-Adrenergic Receptor (B-AR)-looks like adrenalin and nAChR (nicotinic ACh receptor)
-alters signalling programs within cell
NNK mechanism
- Heated/Cured Nicotine –> NNK
= breaks double bond to form =o + N nitroso compound - Body tries to detox foreign substances by hydroxylation and conjugation into a carrier
-cytochrome p450 hydroxylates alpha carbon == to solubilise molecule, conjugate into a carrier and get out of body
-but upon NNK hydroxylation, it falls apart spontaneously - Release of Ch3 - N = N -OH
=Methyl diaxo hydroxide
=very reactive molecule - O6 of guanine attacks the methyl group, causing molecule to fall apart, and form O6methyl Guanine (methyl group on G)
G –> G –> T –> A
Example of Effect of PAH
1/2 worlds popn dinner cooked on smokey cooking fires effects woman and children poorer countries of world -soot exposure without tobacco Smoky cooking fires have high contents/frequency of G-->T Initiator
Example of Effect of NNK
Cancers in people w/o ability to 6Omethylguanine
- enzyme MGMT (Methyl Guanine Methyl Transferase)
- comes from methylation of guanine
- repair enzyme for 6Omethylguanine
- many cancers lack this enzyme, resulting in massive increase in G–>A mutations
NNK effect on cells
- NAChReceptors respond to Nicotine/NNK (Nicotinic ACh Receptor)
a). Sets up Calcium mediated signal into cell
b). Promotes:
-Proliferation
-Survival
-Invasion (if malignant cell)
(signalling through normal receptor, responding to abnormal ligand, acts as a promotor, inducing changes in cells that line the airways) - B-AR receptor
-binds NNK
-sets up signalling pathways to Cyclic AMP cAMP and verascot onocogene
-same Promotion
Overall: Promotor like effects via acting through receptors
NACh Receptors
Contained on multiple cells
a) Brain: contribute to Hibituation
b) Adrenal gland: NNk binding can cause release of Catecholamines (Adrenalin, NA) –>
Indirectly stimulating Adrenergic receptors on epithelial cells
c) Endothelial cells (BV) stimulates when these agents binds to NAChReceptors
-cause ingrowth of new BV
-Angiogenesis promotes tumour growth (no cell can survive w/o BV nearby)
What does Progressive tumour growth require?
Angiogenesis
Endothelial cells (BV) stimulates when these agents binds to NAChReceptors
-cause ingrowth of new BV
-Angiogenesis promotes tumour growth (no cell can survive w/o BV nearby)
Liver Cancer
Freq. due to inflammation
- alcohol
- diet (fat) steatotic disease, generating inflammation, releasing aldehydes from broken down lipids, act as initiators
- fungal toxins in food (food not adequately preserved)
AFB1
-fungal toxins in food (food not adequately preserved)
-produced by aspergious flavus fungal toxin that is present in uncontrolled levels in 2-3 billion people
-responsible for massive proportion of liver cancer
–> Major chemical initiator effecting humans
Synergises with Hep B virus
AFB1 promoting effect
p53 mutation that smoking gun/specific arker for exposure to AFB1
Normally: codon 249 = AGG –> codes for a/acid Argenine in p53
AFB1 exposure: AGT
-foreign lump of organic matter stuck to base
-G doesnt code properly, A put opposite it –> resulting in T opposite A (AGT)
G –> T mutation
(like PAH polycyclic aromatic hydrocarbons)
Encodes for a/acis S (serine)
-underlies loss of growth control in liver cells
Selection of this mutant = expanding clone = HCC (hepato cellular carcinoma)
HBV Hepatitis B promoting effect
a) 1. Induces cell death
- toxic virus, and immune response against it will also kill cells
2. Inflammation
3. Induces cell Proliferation (regenerative)
- when there are cell that contain DNA damage, and divide like crazy, tend to replicate before they can repair their DNA
- DNA damage doesnt get repaired and undergoes proliferation
- or undergo cell death via Apoptosis (p53)
b) X protein
- hepB transcription factor
- effects cell expression:
1) indirectly activates RAS protein to induce proliferation (promoting effect)
2) inhibits p53 –> inhibiting Apoptosis and DNA repair
What is the most important endogenous complete carcinogen?
Chronic Inflammation
-increases cancer rates because:
1. produces Reactive Oxygen species and R Nitrogen species from phagocytic cells (macrophages and neutrophils)
-> DNA damage
2. produces Cytokines (Interlukin 6 and TNF) promoting proliferation (as if wound repair)
-why tumours are like wounds that do not heal
(DNA damage and altered cell signalling)
What is the effect of Hep B Viral Toxins
a) 1. Induces cell death
- toxic virus, and immune response against it will also kill cells
2. Inflammation
3. Induces cell Proliferation (regenerative)
- when there are cell that contain DNA damage, and divide like crazy, tend to replicate before they can repair their DNA
- DNA damage doesnt get repaired and undergoes proliferation
- or undergo cell death via Apoptosis (p53)
What is the effect of Hep B X Protein Transcription Factor
b) X protein
- hepB transcription factor
- effects cell expression:
1) indirectly activates RAS protein to induce proliferation (promoting effect)
2) inhibits p53 –> inhibiting Apoptosis and DNA repair
