7. Tumour initiation and promotion Flashcards
1. Initiation and mutagenesis 2. Mouse skin 2 stage model of chemical carcinogenesis 3. Introduce evidence for multistage development of cancer using colorectal cancer as an example
what is tumour progression?
- the process of normal cells evolving into cells with increasing neoplastic phenotypes
- progression is driven by mutation and epigenetic events that effect genes controlling cell proliferation, survival and other traits associated with malignant cells
what is the main evidence for cancer development being a multistage process?
- age is the highest risk factor for cancer
- suggests you need time to accumulate mutations
- evidenced by the 20 year delay between the increase in smoking and the increase in lung cancer
what are the 4 stages of multistage carcinogenesis?
- initiation event
- promotion
- transformation
- progression
what is initiation?
- a genetic change or mutation in a stem cell
- this is irreversible
what is promotion?
- promoters are usually environmental factors
- stimulates clonal proliferation/expansion of the initiated cell
- this is reversible as promoters are not mutagenic
what is transformation?
- the transition into a malignant cell
- point it becomes cancer
what is progression?
- metastasis
- distribution through the body
what is the Aimes test?
a test to determine if something is a mutagen
what is the process of the Aimes test?
- A test compound is added to a liver cell culture
- metabolic activation to activate the carcinogen
- added to a modified bacteria that needs a supplement to grow
- eventually the chemical will hit the gene which means it can grow without supplement
- lots of colonies = strong carcinogen
- few colonies = weak carcinogen
what is the mouse skin multistage carcinogenesis?
- add a carcinogen/initiating agent to mouse skin
- cause an initiation event
- it can sit there as a mutated cell
- add a TPA to cause inflammation
- inflammation causes expansion of the mutated cell
- becomes cancer
what is a TPA?
- a tumour promoting agent
- not a mutagen but affects gene expression and causes inflammation
- activates many signalling pathways
what are indirect acting carcinogens?
they are metabolised into a carcinogen in the body
eg Benzo(a)Pyrene -> 7,8-diol-9,10-epoxide which binds guanine causing mutation in c-ras protooncogene
how could genetic variation lead to differences in cancer risk response?
Possibly variation in our ability to activate and detoxify the pro-carcinogens into carcinogens and the speed at which we can do it
how can we link carcinogens to specific cancers?
- different carcinogens cause different mutations creating “fingerprints” for each carcinogen
- this was used to prove passive smoking was causing cancer and making it illegal
different c-ras mutations proved in mouse skin carcinogenesis
- 7,8-diol-9,10-epoxide binds to guanine causing codon 12 mutations in tumours
- Dimethylbenzanthracene binds to adenosine causing codon 61 mutations in the tumours
scheme of initiation and promotion of epidermal carcinomas
- normal cell exposed to a carcinogen resulting in an initiated cell
- the initiated cell can sit harmless for ages
- if exposed to repeated rounds of promoter treatment then it can lead to papilloma formation
- if promoter exposure continues then advanced papilloma forms
- advanced papillomas cannot regress but can be stable if promoter exposure stops
- if it doesn’t stop then papilloma becomes carcinomas
Genes and proteins involved in mouse skin carcinogenesis
- classic oncogene RAS occurs in a cell and the proliferates
- addition mutations accumulate including p53
- p53 mutation leads to a rapid increase in mutation due to genome instability
- so much instability that expansion can continue independent of promoters
when does promotion need to happen?
- after the initiation event within a certain amount of time
- need initiation to have clonal expansion due to promoters
- spread out promoter events can not result in cancer and cause regression
- having repeated initiated events without promotion can lead to cancer if a mutation like p53 occurs
what can accumulation of mutations in growth control genes lead to?
natural selection of the fitter varients
how does heterogeneity occur in cancers?
- as the cancers progresses the genome becomes increasingly unstable
- the rate of mutation can be quicker than the rate of expansion
- less fit populations can be outgrown
- means a tumour can be made up of genetically distinct sectors
- making the tumours hard to treat
what is very common?
having initiated cells
how long can it take for an adulthood cancer to develop?
20-35 years
up until what stage are tumours treatable with surgery?
pre-cancerous
what is the best way to reduce colon cancer morbidity and mortality?
to prevent it