Environmental basis of cancer

Question 1

Human cancer

Answer 1

Skin cancer: most common
Lung cancer: most lethal
Hep B induced Liver cancer: 2nd major carcinogen effecting humans

Question 2

Molecular Epidemiology

Answer 2

Links the environmental agents which induce the cancer

Relates enviro to cancer, via studying molecular changes

Question 3

Complete Carcinogen

Answer 3

An agent which alone has the complete capacity to induce cancer

Question 4

History of the Complete Carcinogen

Answer 4

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

Question 5

Classical Carcinogenic model

Answer 5

Demonstrates synergy between 2x environmental components

Initiator and Promotor

Question 6

Classical Carcinogenic model Mouse

Answer 6

1. I = Initiator (PAH)
   Single low (diluted) complete carcinogen
   -diluted so much that cannot cause cancer itself
2. –Multiple doses of P Promotor (phobol esters from plants)
   –synergises with promotor class of carcinogens –>
3. Papillomas
   -benign tumours on skin
   -most regress
4. Fully Malignant SqCC
   -small number of papillomas the fully progress

Question 7

Treatment and Cancer Scale

Answer 7

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

Question 8

Specificity, Duration and Reversibility of Initiator and Promotors

Answer 8

1. Specificity about order: Initiator has to come first
2. 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

Question 9

Mechanism of Initiators

Answer 9

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

Question 10

Mechanism of Promotors

Answer 10

(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

Question 11

Initiator summary

Answer 11

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)

Question 12

Promotor Summary

Answer 12

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

Question 13

3x types of Skin cancer

Answer 13

1. Basal cell carcinoma
   - most common cancer of caucasians
2. SqCC
   - Basal CC rel. more common
3. Melanoma
   - SqCC more common
   - hits and kills in younger people

Question 14

Skin cancer carinogen

Answer 14

UV

• UVB and UVA
• exposed to it all the time

Question 15

UVB

Answer 15

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

Question 16

UVA

Answer 16

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

Question 17

Sunscreen

Answer 17

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

Question 18

Mutational spectrum re Skin cancer

Answer 18

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)

Question 19

UV onto Skin (Initiator)

Answer 19

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

Question 20

Overall Initiator (UV) mechanism

Answer 20

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.

Question 21

UV onto Skin (Promotor)

Answer 21

1. 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

Question 22

What patches of skin can you end up with when you’re older?

Answer 22

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)

Question 23

How is UV a promotor

Answer 23

Selects for cells which accumulate p53 mutation

Question 24

What is the consequence of been savagely sunburnt as a child?

Answer 24

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

Question 25

Old people skin

Answer 25

Patchwork of mutant clones | -shows you can tolerate a certain amount of mutations

Question 26

Lung Cancer Carcinogen

Answer 26

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

Question 27

Lung Cancer Subtypes

Answer 27

1. Adenocarcinoma LC: 40% - Bronchial epithelial, Surfactant secreting cells - most likely for non-smokers 2. SqCC LC: 30% - Bronchial (large airways) epithelial cells 3. Anaplastic LC: 10% - poorly differentiated adenocarcinoma, SqCC - cannot tell what they are as so badly differentiated 4. Small cell LC:20% - Bronchial Endocrine cells

Question 28

Cancer of non-smokers

Answer 28

Adenocarcinoma | -SqCC, Anaplastic and Small cell almost purely Tobacco induced

Question 29

Tobacco Carcinogenic agents

Answer 29

60 known carcinogenic agents in Tobacco smoke 1. PAH - doesn't matter what you smoke, if you breath in partially combusted Plant matter, it will contain PAH 2. 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

Question 30

Tobacco Carcinogens as a complete Carcinogen

Answer 30

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

Question 31

NNK mechanism

Answer 31

1. Heated/Cured Nicotine --> NNK = breaks double bond to form =o + N nitroso compound 2. 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 3. Release of Ch3 - N = N -OH =Methyl diaxo hydroxide =very reactive molecule 4. O6 of guanine attacks the methyl group, causing molecule to fall apart, and form O6methyl Guanine (methyl group on G) G --> G --> T --> A

Question 32

Example of Effect of PAH

Answer 32

``` 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 ```

Question 33

Example of Effect of NNK

Answer 33

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

Question 34

NNK effect on cells

Answer 34

1. 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) 2. 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

Question 35

NACh Receptors

Answer 35

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)

Question 36

What does Progressive tumour growth require?

Answer 36

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)

Question 37

Liver Cancer

Answer 37

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)

Question 38

AFB1

Answer 38

-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

Question 39

AFB1 promoting effect

Answer 39

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)

Question 40

HBV Hepatitis B promoting effect

Answer 40

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

Question 41

What is the most important endogenous complete carcinogen?

Answer 41

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)

Question 42

What is the effect of Hep B Viral Toxins

Answer 42

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)

Question 43

What is the effect of Hep B X Protein Transcription Factor

Answer 43

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