Carcinogenesis Flashcards
Features of a benign tumour?
Slow growth
Non-invasive
No metastasis
Features of a malignant tumour?
Rapid growth
Invasive
Potential for metastasis
What are the stages of carcinogenesis?
Initiation
Promotion
Progression
What happens in initiation?
Unrepaired DNA damage due to a carcinogenic initiator
What happens in promotion?
Coronal expansion from rapid proliferation leading to benign tumour formation
How long does promotion take?
10 to 30 years
How do carcinogens cause mutations?
After being metabolised, it forms a DNA adduct (covalent bond) which causes a mutation
What can be a mutagen and how do they cause the damage?
A virus causing insertional mutagenesis
Chemicals causing DNA adducts
UV and ionising radiation causing single and double strand breaks
Function of a proto-oncogene?
Cause cell growth and gene transcription
Normal function of a tumour suppressor gene?
Cell repair
Cell cycle control
Cell death
Difference between a tumour initiator and promoter?
Initiators are mutagens
Promoter causes multiplication of the damaged cells
If exposed to a promoter first and then the initiator, nothing will happen
Example of a promoter?
Oestrogen for breast cancer
Androgens for prostate cancer
What can be an intracellular cause of a gene mutating?
Misinterpretation of code
Polymerase slippage
Base malalignment
Ineffective repair with age
What can be environmental causes of mutations and how?
Carcinogens which bind to DNA and alter the sequence, affecting replication
Ionising radiation/UV can cause strand breaks or cross-links
DNA can be translocated to transcriptionally active regions
Give examples of initiators
Chemical carcinogens Oncogenic viruses Radiation UV light Oxygen free radicals
Give examples that can cause mutations in genes
Alteration of bases Strand breaks Base oxidation Deletion of bases Deletion of chromosome fragments Adducts of carcinogen and base Chromosome translocation/rearrangement Gene amplification
Examples of some chemical promoters?
Phorbol esters
Phenols in tobacco tar
Xenoestrogens found in insecticides
Saccharin
Give inflammatory examples of promoters
Chronic irritation from eg pipe smoking
Endoparasites eg schistosoma haematobium causing bladder cancer
Bacterial infection eg H pylori
Which drug can be given to block oestrogen receptors?
Tamoxifen
What is cancer?
A group of diseases sharing similar characteristics, all of which show inappropriate proliferation, invasion and metastasis
What is cell signalling required for?
Cell cycle progression Proliferation Inflammation Pro/anti-apoptosis Metastasis Invasion
What is cell signalling controlled by?
Cell surface receptors Ligands Cascade of intracellular signal transduction Proteins Transcription factors Inhibitors Mitogens Cytokines
What can be changed about cell signalling pathways so that they promote cancer?
Increase in receptor expression
Mutant receptor expression (self-activating)
Down-regulation of inhibitory proteins/mechanisms
Increased ligand expression
Increased expression of transcription factors
What are the six hallmarks of cancer and how does it do it?
Induce angiogenesis - active VEGF signalling
Evade growth suppressors - inactivate cell cycle checkpoint
Sustain proliferative signalling - constitutively activate growth factor signalling
Activate invasion and metastasis - loss of cell-to-cell interactions
Replicative immortality - inactivated cell death pathway
Resistance to cell death - activated anti-cell death signalling
Other than the six hallmarks of cancer, what are 4 more important features recently discovered?
Tumour-promoting inflammation
Avoid immune destruction
Genome instability and mutation
Deregulating cellular energetics
General risk factors for cancer?
Genes Carcinogens Radiation Chemicals eg abestos Viruses eg HPV Diet Alcohol Smoking
What are some carcinogens in different foods?
Heterocyclic amines (meat) Toxins Inflammation/oxidative stress inducers Hot drinks/food Alcohol
Which foods specifically are carcinogens?
Red meat Animal fat Salted fish BBQ/chargrilled foods Salt-preserved foods Contaminated foods (fungus)
What evidence is there that foods affect cancer risk?
Migration studies
Intervention trials
What increases heterocyclic amine concentration?
Cooking meat and increasing the cooking time
Metabolised to the liver to genetoxic metabolites
How does barbecuing meat increase cancer risk?
Burns fat to produce polyaromatic hydrocarbons which require metabolic activation
Adducts to DNA bases - p53
How do high carb foods increase cancer risk?
If they are roasted or baked eg cereal, coffee, bread, crisps
Contain acrylamide which is a genotoxic metabolite which adducts to DNA
What is chemoprevention?
Inhibition, retardation or reversal of the carcinogenic process
Examples of drugs in chemoprevention?
Tamoxifen
Celecoxib (COX-2)
Aspirin (COX)
Herceptin (EGFR Ab)
What is a direct acting carcinogen?
One that binds directly to DNA
What are procarcinogens?
Require metabolic activation
