Principles of cancer Flashcards
What is meant by the term ‘tumour heterogeneity’?
Tumour develops through continual process of clonal expansions, leading to mass mad eup of multiple clones
When might a new clone arise during tumour formation?
- If a mutation occurs that increases the evolutionary fitness of the cell relative to others
- A change in the tissue environment favours the phenotypic capabilities of a cell/clone carrying a particular mutation (e.g. patient starts taking a targeted therapy - creates selective pressure which favours cells with resistant mutation
Give an example of a mutation acting as both a driver and passenger
EGFR p.Leu585Arg
Driver in lung tumours - increased proliferation and survival due to constitutive activation of the MAPK signalling pathway
Passenger in KRAS-mutant CRC - MAPK pathway already over-activated by KRAS driver
Give an example of a passenger mutation becoming a driver due to a change in environmental factors
EGFR p.Tyr790Met
EGFR TKI therapy favours cells that provide TKI resistance, previously mutation did not provide a selective advantage
Name the six main hallmarks of cancer
- Sustained proliferative signalling
- Evading growth suppressors
- Resisting cell death
- Enabling replicative immortality
- Inducing angiogenesis
- Activation of invasion and metastasis
How can a cell acquire the ability of sustain continuous growth signalling?
Increased amount of growth signal receptors on cell surface (e.g. EGFR amplification)
Production of mutant proteins within growth signalling pathway that are constitutively active (e.g. KRAS, BRAF, EGFR, PIK3CA
What is the role of RB and TP53 in negatively regulating cell proliferation?
TP53 detects DNA damage/other stress and triggers growth arrest, DNA repair or APOPTOSIS
RB inhibits cell cycle progression from G1 to the S phase
What is the role of a diagnostic marker in tumour profiling?
Presence/absence of a marker confirms or excludes a diagnosis
What is the role of a prognostic marker in tumour profiling?
Presence/absence of a marker provides info on likely behaviour ot a tumour (e.g. aggressivity, metastatic potential)
What is the role of a predictive marker in tumour profiling?
Presence/absence of a marker predicts whether a patient is likely to respond to a particular treatment
How does genome instability enable tumour progression?
Increased mutation rate increases likelihood of further enabling mutations, due to:
- Defects in the DNA repair machinery (MSH2, MSH6, MLH1, BRCA1/2
- Defects in cell surveillance systems that detect stress and trigger apoptosis (TP53)
How does inflammation enable tumour progression?
Inflammatory response is seen in neoplastic tissue
Supplies useful molecules to the tumour microenvironment (growth factors that sustain proliferative signalling, survival factors that limit cell death)
