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POM - mine > 31 - Environmental Basis of Cancer > Flashcards

31 - Environmental Basis of Cancer Flashcards

1
Q

What to know

A
  • 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
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2
Q

Carcinogen

A

Cancer causing agent

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3
Q

Complete Carcinogen

A

Any agent that on its own at a sufficient dose will cause cancer

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4
Q

EG of a complete carcinogen

A

Polycyclic Aromatic Hydrocarbons (soot in chimney sweeps) > SqCC (squamous cell carcinoma)

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5
Q

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

A
  • 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)
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6
Q

Just initiator

A

tumor

no

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7
Q

Multiple promoter

A

tumor

no

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8
Q

initiator single low dose (can’t cause anything by itself) followed by several doses of P

A

papillomas > then SOME SqCC

Strong synergy between the 2 agents

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9
Q

Multiple promotor followed by 1 dose of initiator

A

Nothing

Sequence of application of the 2 agents is important

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10
Q

Initiator, leave long gap then promoter

A

Tumours

Initiation seems to be an irreversible process

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11
Q

Initiators are…

A

Irreversible in their effect

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12
Q

Promoter spaced out beyond a certain time period

A

Tumours don’t develop

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13
Q

Promoters are…

A

Reversible signal

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14
Q

Initiators…

A

Environmental agents that target DNA, induce mutations and alter gene structure

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15
Q

Promoters…

A

Target proteins, so change intracellular signalling pathways and alter gene expression

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16
Q

Synergy between initiators and promoters

A

Initiators deliver potentially carcinogenic damage. Promoters selectively stimulate the growth of initiated cells

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17
Q

Example of a promoter

A

Phorbol Ester

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18
Q

What % of new cancers are skin cancers?

A

80% - due to UV light (carcinogen)

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19
Q

UVB and UVA wavelength

A

UVB: short
UVA: long (blue)

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20
Q

UVB and UVA penetrence

A

UVB - weak penetrence so is absorbed earlier (more energetic)
UVB has strong penetrence

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21
Q

UVB and UVA sunburn

A

UVA doesn’t often cause sunburn (weak)

uvB does cause sunBurn (STRONG)

22
Q

UVB and UVA effect on cells

A

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)

23
Q

UVB and UVA class

A

UVA - weak complete carcinogen (more like a promoter)

UVB is a complete carcinogen

24
Q

3 types of carcinoma caused by UV radiation as a complete carcinogen

A
  • basal cell carcinoma
  • squamous cell carcinoma
  • melanoma (rare but affects young people so lots of life years lost)
25
Q

How can the type of initiator be inferred in BCC and SqCC?

A

The type of initiator can be inferred by the type of mutation found. I.e. P53

26
Q

What gene is frequently found mutated in cancers of sunlight exposed skin?

A

p53

27
Q

How does p53 work in cancers due to skin exposure to

A
  • C to T transitions especially in dipyridine sequences

- CC to TT tandem mutations rare in any other cancer

28
Q

p53?

A

TSG - restrains abnormal growth
Often mutated in skin cancers
The types of mutations in P53 give an indication of what the carcinogen is

29
Q

p53 mutations

A

C > T esp at dipyridimine sites

CC > TT (rare)

30
Q

How do p53 mutations work

A
  • 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
31
Q

What happens after UV exposure

A
  • 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
32
Q

UVA?

A

Doesn’t cause sunburn but acts as a promoter

33
Q

homo/wild type p53
hetero
homo mutant

A 
efficient apoptosis (peeling sunburn)
reduced p53 mediated apoptosis expanding mutants
loss of apop > malignant change
34
Q

What is the most intensively studied carcinogen

A

tobacco
most important preventable casue of morbidity and mortality (30% of cancers and 90% of lung cancers)
CVD biggest killer from tobacco

35
Q

How many carcinogens in tobacco

A

60

PAH especially

36
Q

PAHS

A
  • in any partially combusted plant material
37
Q

What kind of mutation do PAHs tend to cause in the P53 gene

A

G>T
(C>T in skin cancer)
Also acts as a promoter as binds AhR

38
Q

NNK? Nicotine DERIVED products

A
  • Carcinogen

- G > A and binds BAR (adrenaline rececptor) and nAChR

39
Q

Is nicotine a carcinogen

A

no but it can be transformed at high T into NNK (carcinogen)

Break down product

40
Q

How does nicotine acts as a carcinogen

A
  • 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
41
Q

What is the mutation with NNK

A

G > A

UVB is C>T PAH is G > T

42
Q

MGMT?

A

methyl guanine dna methyl transferase

High amount of lung cancers with G>A mutation seen in people without this repair enzyme

43
Q

Where else is the G>T mutation seen besides people who don’t smoke?

A

People who cook over smoking fire (PAH)

44
Q

How does NNK also affect cell signalling

A
  • 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
45
Q

NNK

A

Nitrosaminoketone

46
Q

2 carcinogens for HCC

A
  • aldehydes (inflam > breakdown of lipids)

- fungal toxin (alfatoxins from Aspergillus flavus)

47
Q

What toxin is a carcinogen for HCC

A

Alfatoxins from Aspergillus flavus

48
Q

How does aflatoxins work

A
  • alkylates the end G in AGG
  • (AFB)G-C
  • A replaces the C
  • (AFB)G-A
  • T -A
49
Q

What is the promotor and what is the initiator

A
  • initiator is aflatoxin by aspergillus flavus (AGG>AGT)

- promoter is HBV (hep B virus)

50
Q

How does HBV act as a promoter

A
  • 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
51
Q

How does HBV act as a promoter

A
  • HBV makes X protein
  • inhibits repair
  • binds P53 and indirectly activates RAs protein contributing to outgrowth of abnormal cells
52
Q

What is the most important endogenous complete carcinogen in our bodies?

A

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)

POM - mine (17 decks)

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