3 - Aetiology of Carcinogenesis Flashcards
Carcinogenesis
The process by which normal, healthy cells transform into cancer cells
Somatic mutation theory
- Cancers arise from mutations in individual cells, passed on through division
- Clinically observable cancer is result of accumulating multiple mutations
Mutator phenotype
An acquired increase in rate of mutation
What does first mutator acquisition relate to
- Increased cell division
- Abnormal DNA replication
- Damaged DNA repair mechanisms.
Lethal mutation
Disruptive in a manner that harms or kills the cell
Passenger mutation
Consequential, no selective advantage
Driver mutations
Provides a selective advantage
Multi step process of mutation
- Cancer causing mutations are cumulative but randomly ordered
- Mutation can occur in any cell at any time
- Most likely to occur during DNA replication
- Will only be passed on if cell divides
Stepwise mutations
- Results in heterogeneity between tumours in an individual with metastatic disease or within a single tumour
- Has implications for therapy (one cell with resistance survives treatment then replicates so cancer comes back resistant)
Examples of tumours co-opting existing cellular pathways
- VEGF disruption can change angiogenesis
- P53 disruption can interfere with apoptosis
- MAPK signalling can impact on tissue invasion, growth signals self-sufficiency AND proliferation
Selective pressures of tumours
- Immune system
- Tumour suppressor genes
- Microenvironment (e.g. anaerobic respiration under hypoxia)
Feedback loop of cancer
Less tumour cell death –> more proliferation –> more rounds of DNA replication –> more chance of passing mutations on –> more opportunity for mutation and instability
Proto-oncogenes typically are one of
- Cell division stimulators
- Differentiation blockers
- Apoptosis inhibitors
- Components of signalling pathways
- Growth factors.
How do proto-oncogenes become oncogenes
When expressed at increased levels, resulting from either:
- Amplification leading to more copies of the gene
- Translocation to a more active promotor
- Mutation resulting in a fusion protein with oncogene activity
How many oncogenes currently known
> 40
Examples of oncogenes
MYC and RAS
MYC
- Transcription factor
- Overexpressed/activated in >50% of human cancers
- Coordinates many cellular processes (e.g. angiogenesis)
- Proliferative arrest
- Blocks senescence and differentiation
MYC addiction
- Tumour survival often depends on high MYC
- Not sufficient alone for carcinogenesis
RAS
- GTPase signalling proteins
- 3 RAS genes
- RAS on/off activity is sped up by regulatory proteins
RAS regulatory proteins
- Guanine nucleotide exchange factors (GEF) catalyse exchange of GDP with GTP (RAS “switched on”).
- GTPase-activating proteins (GAP) catalyse hydrolysis of GTP to GDP (RAS “switched off”).
- Mutant RAS don’t allow GAP to coordinate hydrolysis (RAS is stuck ‘on’)
3 RAS genes
- KRAS, NRAS, HRA
- RAS mutants are 85% KRAS
RAS effects
- Cell survival and growth
- Transcription
- Cell cycle progression
- Cell migration
Tumour supressor genes
- “anti-oncogenes”
- Problem if these are knocked out
- Often requires both alleles being knocked out
- Hereditary susceptibility
- Often have suppressive or regulatory activity
Suppressive or regulatory activity of tumour suppressor genes
- Control proliferation
- Initiate apoptosis if DNA damage is detected
- Regulate adhesion i.e. stop metastasis