Cancer 2) Hallmarks of cancer Flashcards
Why is it important to study cancer?
1 in 3 people will develop cancer
1 in 4 men and 1 in 5 women will die of cancer
Incidence of cancer increases with age
What has studying cancer revealed?
Growth of normal cells
Pathways of controlling normal growth
Mechanisms of cell death
Mechanisms of tissue regeneration
What is the evidence that cancer is genetic?
Age evidence
Carcinogens are mutagens
DNA of tumours contains many and varied aberrations
Mutations in specific genes generate cells bearing hallmarks of cancer
What are the features of malignancy?
Uncontrolled growth
Capacity to infiltrate normal or damaged tissues
Capacity to spread to other sites
Capacity to cause illness and/or death
What are the cellular hallmarks of cancer?
Autonomy from growth signals Evasion of growth inhibitory signals Evasion of apoptosis Unlimited replicative potential Angiogenesis Invasion and metastases
What cancer do viral HPV 16 and 18 cause?
Cervical cancer
What is the role of E6 and E7 proteins in cervical cancer?
Both required for carcinogenesis
E6 binds p53 and targets it for degradation
E7 binds, phosphorylates and inactivates Rb protein
What cancer does HTLV-1 cause?
Adult T-cell lymphoma
What virus causes Burkitt’s lymphoma?
EBV
What do UV radiation and chemical carcinogens do?
Interact with components of DNA to cause damage
Damage can be to bases or sugar-phosphate backbone
Damage can be repaired, misrepaired or unrepaired
What are oncogenes?
Mutated version of normal human proto-oncogenes
Dominant, not normally inherited
How can oncogenes affect gene function?
Increase level of expression of the gene
De-regulate expression of the gene
Alter protein product so it’s more active
Alter protein product so it’s not degraded
What do oncogenes do to malignant pathways?
Increase activity of pro-malignant pathways - cell growth, replication, angiogenesis, invasion, metasases
Inhibit activity of anti-malignant pathways - apoptosis, cell cycle regulation, growth inhibition
Give examples of oncogenes
erbB1
erbB2
ras
What does erbB1 encode and what do mutations do?
Encodes EGFR
Oncogenic mutation means EGFR is activated in absence of EGF
Causes overactivity of RAS-MAPK pathway and over expression of growth promoting genes
What does mutated ras cause?
Loss of GTP-ase activity of RAS protein
RAS remains bound to GTP and is constitutively activated
What are tumour suppressor genes?
Suppress pro-malignant processes: apoptosis, cell cycle checkpoints, growth inhibition, DNA repair
Give examples of tumour suppressor genes
p53
BRCA1 and BRCA2
APC
What is the consequence of mutated p53?
Cells proceed to mitosis with damaged DNA
Cells fail to undergo apoptosis when damaged
Incomplete DNA repair
Tumour angiogenesis persists causing tumour growth
What is Li-Fraumeni syndrome?
Inherited p53 mutation
Grossly elevated cancer risk
Causes sarcoma, breast cancer, leukaemia and brain tumours at early age
Describe APC mutations
Inherited mutations responsible for familial adenomatous polyposis coli
1 mutation inherited, other is spontaneous mutation in colonic epithelium
What is FAP?
Develop multiple colonic polyps in early adulthood which predispose to cancer
Very high risk of colon cancer
Describe the chain of events leading to colorectal cancer
Normal colonic epithelium APC mutation causes small adenoma K-ras DCC mutation causes large adenoma p53 mutation causes carcinoma Aneuploidy causes metastases
What do normal growth inhibitory signals do?
Downregulate growth receptors
Inhibit transcription
Inactivate or degrade signalling proteins
Phosphatases inhibit kinase signalling cascades
Compete with growth mediating proteins
What is the mechanism of apoptosis?
Cytoplasmic shrinkage
Nuclear breakdown
Cleavage of structural proteins
Membrane blebbing, apoptotic bodies
How can apoptosis be activated?
Extrinsically e.g. in response to TNF or intrinsically in response to oxidative stress or DNA damage
Give an example of an anti-apoptotic protein
Bcl-2
Give examples of pro-apoptotic proteins
Bax
p53
What is the consequence of p53 mutation on apoptosis?
Renders cells less likely to undergo apoptosis
Mutant cells are more likely to develop further mutations
Mutant cells are more resistant to cancer treatment
How does cancer cause unlimited replicative potential?
Telomerase is unregulated which maintains length of telomeres and stops them shortening so they don’t undergo cellular senescence or apoptosis
What is a stimulant of angiogenesis?
Vascular endothelial growth factor (VEGF)
Hypoxia
How do tumour cells break free from inter and extracellular connections?
Via abnormal expressions of integrins
Invasive capacity mediated by matrix metalloproteases and inhibited by TIMPs
What are the emerging hallmarks of cancer?
Deregulating cellular energetics
Avoiding immune destruction
Genome instability and mutation
Tumour-promoting inflammation
What drugs are given to prevent proliferative signalling?
EGFR inhibitors
What drugs are given to stop evasion of growth suppressors?
Cyclin-dependent kinase inhibitors
What drugs are given to stop cancer avoiding immune destruction?
Immune-activating CTLA4 mAb
What drugs are given to stop cancer enabling replicative immortality?
Telomerase inhibitors
What drugs are given to stop tumour promoting inflammation?
selective anti-inflammatory drugs
What drugs are given to stop cancer activating invasion and metastases??
Imhibitors HGF/c-MET
What drugs are given to stop cancer inducing angiogenesis?
Inhibitors VEGF signalling
What drugs are given to stop genome instability and mutation?
PARP inhibitors
What drugs are given to stop cancer resisting cell death?
Propapoptotic BH3 mimetics
What drugs are given to stop cancer deregulating cellular energetics?
Aerobic glycolysis inhibitors
