environmental basis of cancer Flashcards
complete carcinogen
any agent which at a sufficient dose will cause cancer by itself
both initiator and promoter effects
e.g. squamous cell carcinomas
what significance does the sequence of application of the two agents (initiator and promoter) have
if you give a small dose of initiator followed by promoter then tumour occurs.
However, if you give a dose of promoter before initiator no tumour arises
initiator
- are environmental agents which target DNA
- induce mutations (change gene structure)
- must be present for tumour to form
- Irreversible - once the damage to DNA is done it’s done
promoter
- target proteins, e.g. proteins, enzymes
- alter signaling pathways (change gene expression)
- must also be present for a tumour to form
- Reversible - promoters are ineffective if you spread out the stimulus. (The stimuli do things like make cells want to divide)
- stimulate growth of initiated cells
UVB
- short wavelength
- weak skin penetration
- strong sunburn inducers
- damages DNA
- strong complete carcinogen
UVA
- long wavelength
- strong skin penetration
- weak sunburn inducers
- generates reactive oxygen species
- promoter (weak complete carcinogen)
p53 in UVB
tumour suppressor gene (regulates cell responses to stress)
- frequently mutated in cancers of sunlight-exposed skin
- mutations result in C–>T (especially in dipyrimidine sequences) and CC—> TT transitions
PAH
- carcinogen associated with tabacco
- are present in any partially combusted material (any form of smoking)
- mutation G –> T (initiator activity)
- bind receptors AhR
the phenotype of a homozygous wild-type p53 (+/+)
efficient p53 mediated apoptosis (‘peeling sunburn’)
the phenotype of a heterozygous, one mutant allele, p53 (+/-)
reduced p53-mediated apoptosis, expanding mutant clones with every episode of sunburn
the phenotype of a homozygous mutant p53 (-/-)
loss of apoptosis and cell cycle arrest in response to stress; malignant change
NNK (nicotine derivative)
- not a carcinogen
- G —> A mutation
- bind receptors B-AR & nChR
- its breakdown product can form carcinogen
how can NNK suppress apoptosis
breakdown products of nicotine signal through receptors (nAChR & b-AR) can induce a signalling pathway stimulating oncoproteins e.g. RAS (alters transcriptional activity). As a result, this can give signals to stimulate proliferation, suppress apoptosis
initiator of hepatocellular carcinoma
- aldehydes (resulting from inflammation from ROS)
- mutation in p53 gene at codon 249
- AGG —> AGT
promoter of Hepatocellular carcinoma
- HBV, causes cell necrosis –> chronic inflammation –> regeneration / proliferation (outgrowth of abnormal clone)
- expresses HBX which:
inhibits DNA repair
escorts p53 out of nucleus (no function)
activates RAS
