Lecture 1 - Introduction Flashcards
What is the life cycle of a cancer?
Cell with genetic mutation Hyperplasia Dysplasia in situ cancer Invasive cancer
What are the 8 hallmarks of cancer?
Self sufficiency in growth signals Insensitivity to growth inhibit signals Tissue invasion and metastatis capability Limitless replicative potential Sustained angiogenesis Evasion of programmed cell death Reprogram energy metabolism Evading immune system
What are the two enabling events?
Loss of genome surveillance and checkpoint control
Why is it so difficult to treat cancers?
There is an infinite number of mutations that can cause a tumour
What does it mean that tumours are often heterogeneous?
Often made up of lots of different cell types
How do two independent cancers appear nearby seperated by normal tissue?
Because a cancer cell is dividing uncontrollably there is a higher chance one of the new cells has another mutation. This can branch off and form another cancer.
What does a mitogenic signal do to a cell?
Moves it from a quiescent state (g0) into a proliferative state (s phase)
What kind of molecules can be used in signalling for growth factors?
Diffusible growth factors
Extracellular matrix components
Cell to cell adhesion molecules
Give a short overview of what happens when a diffusible growth factor binds to a cell
- Ligand binding
- tyrosine kinase domains dimerise
- Domains phosphorylate other proteins
- Signal transduced
Whatare 3 ways oncogenes can mimic growth signalling?
Act at the level of the signal
The receptor
Disrupting signal transduction
What is the difference between oncogenes and tumour suppressor genes?
Oncogenes are GOF mutations that promote proliferation.
Tumour suppressor genes are LOFs in genes that restrain proliferation or guard genome.
What kind of mutation is an oncogene usual;y?
Dominant
What kind of mutation are tumour suppresor genes?
Recessive (often underlie familial cancers)
What is Her2?
A receptor tyrosine kinase of the epidermal growth factor receptor thats overexpressed in 30% of breast cancers
What happens in Her2 cancers?
Receptor is overexpressed making cells hypersensitive to ligand.
Activates intracellular kinases which have effects on apoptosis and proliferation.
What is herceptin?
A monoclonal antibody that extends the life of Her2 breast cancer patients
What is RAS?
An intracellular switch that is fixed into the ON position in cancers.
What inactivates RAS?
Hydrolysis of GTP to GDP by GAP
What activates RAS?
GDP to GDP triggered by GEF
What does a mutation is RAS cause?
Structural alterations that generate extended firing periods.
How many cancers involve RAS?
25% of human cancers
What is a viral oncogene?
Some viruses have picked up proto-oncogenes and incorporated them into the genome.
What does a viral oncogene do?
Host cells harbouring the virus gain a growth advantage (propagating the virus)
How is the expansion of cell populations normally controlled?
Programmed cell death
What is phosphatidyl serine?
A label put onto cells that have gone through apoptosis marking it to be cleared by macrophages
What can lead to apoptosis?
Extrinsic - Responding to signalling imbalances (survival signals, death signals, overexpressed oncogenes)
Intrinsic - Responding to DNA damage or hypoxia
What are some pro-apoptotic factors that lead to released cytochrome C in the mitochondria
Bax
Bak
Bid
Bim
What are some anti-apoptotic factors?
Bcl-2
Bcl-XL
Bcl-W
How were the Bcl-2 family (anti-apoptotic) first discovered?
Identified as half of chromsomal translocation in B-cell lymphoma that up regulates Bcl2 and increases anti-apoptotic activity
What is another way to evade apoptosis?
Loss of p53 - mutant cells cannot die in response to DNA damage
What detemines the maximum size of the tumour?
Diffusion from blood - cells must be within 100 microns of a capillary
How does a developing tumour encourage blood vessels to grow (angiogenesis)?
- An endothelial cell is signalled by VEGF released from a tumour nearby.
- Endothelial cell moves and develops a capillary sprout
- Cells behind replicate and hollow out vacuoles which join creating a tube to the tumour
What is VEGF?
Angiogenic signal used in normal development and by cancer cells
What is HIF?
Protein that regulates expression of genes involved in angiogenesis
What does HIF do in normal oxygen (normoxic) conditions?
One of its prolines is hydroxylated which is recognised by protein complex containing Cul2 (E3 ligase) which destablises the protein.
One of its asparagines is hydroxylated preventing binding of transcriptional coactivators
What happens to HIF during hypoxia?
Unhydroxylated HIF is stabilised (no Cul2) and can bind to coactivators (p300) leading to transcription
Outline metabolism in the presence of oxygen
In the presence of O glucose is metabolised by glycolysis in to pyruvate then oxidised to CO2 in the mitochondria by oxidative phosphorylation
What are the effects of chemotherapy?
Stops any rapidly proliferating cell.
This is why we lose our hair
Outline anaerobic glycolysis
Glucose broken down to pyruvate then to lactate
How do rapidly proliferating cells prefer to metabolise?
85% by anarobic glycolysis
Why do cancer cells convert glucose to lactate regardless of whether oxygen is present (not an efficient way to generate ATP)?
To fuel cell growth and division.
Aerobic glycolysis allows diversion of glycolytic intermediates into biosynthetic pathways required for assembling new cells.
How does the immune system deal with cancerous cells?
Natural killer (NK) cells target based on aberrant cell surface proteins and secrete cytokines to recruit macrophages to absorb dying cell
How can tumour cells inhibit NK cells?
Release transforming growth factors beta
What is immune privilege?
Tumours that have evolved ways to change the immune system
How does the FasL system usually work?
FasL on surface of cytotoxic T cells triggers trimerisation of Fas receptors on target cell - leads to apoptosis
How can cancer cells use immune privilege to avoid the FasL system?
- Down regulate Fas receptor
- abnormalities of signal transduction proteins
- downregulation of caspase 1, Bax or Bak
- Upregulation of Bcl2
- Express FasL to counterattack
Why do transplant patients get cancer easier?
Immunosuppressed
What is it called when the cell has reached the Hayflick limit?
Senescence
What happens during crisis?
Mass of senescencing cells die
How many cells escape crisis?
1 in 10^7
What is crisis provoked by?
Eroded telomeres
What is the end replication problem?
DNA polymerase can only add nucleotides on 3’ end so lagging strand gets shorter after each cell cycle
What does telomerase do?
Makes a template on the 3’ end so telomeres do not decrease in length
How many cancers have increased telomerase?
90%
What karyotype of chromosomes is shown in cancers?
Fusion and repair by non-homologous end joining affecting expression of other genes (change relationship between genes and promoters)
How can you visually show the end joining and juggling of chromosomes in cancers?
Put differently coloured tags on each chromosome
