What are the 8 (previously 6) commonly acquired traits of cancer causing cells?
1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhibitory signals
3) Tissue invasion and metastasis capability
4) Limitless replicative potential
5) Sustained angiogenesis
6) Evasion of programmed cell death
7) Reprogramming of energy metabolism
8) Evading immune system
Name two enabling events
Loss of genome surveillance and checkpoint control Destabilisation of nuclear organisation
Why are there so many ways to acquire the same trait?
Mutation of several pathways leads to same consequence for the cell In each pathway mutation of several different genes or proteins can have same effect
What three measures are used in classifying cancers? Why is this not the best way?
Site of origin
Age of onset
Does not look at molecular level
Why do stem cells require fewer mutations on average to become a cancer cell?
Already have unlimited proliferative ability
Why are most tumours described as heterogeneous?
Made up of both neoplastic and pre-neoplastic cell populations
How can two independent cancers come from the same origin?
Same starting mutation but different mutation later on lead to them being separated by healthy tissue which has not developed the caner causing mutation
What do normal cells require to move from quiescence to profilerence?
Mitotic signal; paracrine or endocrine
What are the steps from a mutation to fully invasive cancer
1) Cell acquires genetic mutation - which promotes or allows proliferation 2) Hyperplasia 3) Dysplasia 4) In situ cancer 5) Invasive Cancer - with its own blood supply
How are external signals transmitted into the cell?
Transmembrane Receptors- which then dimerize and phosphoryalte each others tyrosine domains and start an signal transuction pathway
What types of singalling molecules are involved in mitotic signalling?
1) Diffusbale growth factors
2) Extracellular matrix components
3) Cell-to-cell ahgesion/interaction moleclues
How can oncognenes hijack these signal pathways?
Mimicking normal growth signaling
Code forconstitutively active (ligand independent receptors)
Disrupt signal transduction
What are oncogenes?
Gain of function mutations in genes that promote cell proliferation
What are tumour supressor genes?
Loss of function mutations in a genes that restrain cell proliferation or guard the genome
Recessive mutations (often underlie familial cancers)
Outline 2 examples of how cancer cells can de-regulate and acquire self-suffiency in growth signals
Example 1: the ErbB2/Her2/Neu
Overexpression of receptor = hypersensitivity to ligand. Acitvates intracellular kinase which has complex set of effects on both apoptosis and proliferation
Example 2: RAS
An intra-cellular switch protein which can be permanently on due to mutation. When GDP is bound the protein is inactive whereas GTP bound RAS is active. The swtiching between the two have effects on the shape of the entire protein, with active RAS being able to bind down-stream proteins in cell signalling pathways. in non-cancer cells RAS will hydrolyse GTP to switch off; this is dependent on RAS-GAP, inserting an argiunine side chain directly into the active site, which work with threonine and glutamine, of the RAS itself, to promote GTP hydrolysis.
What is herceptin?
Monocolonal antibody that blocks Her2 receptor and extends life in breast cancer patients
Howvere, the life extension is only for months and the quality of life is severed inpacted
What percentage of all cancers have RAS mutations?
What are viral oncogenes?
Some viruses have acquired proto-oncogenes which they will pass onto host cells; conferring a growth advantage to the cell, helping to propagate the virus but causing cancer in the host.
What is heterotypic signalling?
Signalling between cancerous and non-cancerous neighbours.
Neighbours may co-evolve with tumour cells to sustain their growth
What happens during apoptosis and how long will it take?
-Disruption of cell membranes
-Structural filaments broken down
- Debris is phagocytosed
The process will take approximately 24hours
What are the two types of trigger for apoptosis?
Extrinsic singal - Respond to signalling imblances of survival signals and death signals
Intrinsic Signals - Respond to DNA damage and hypoxia
How do these tirggers lead to apoptosis?
Feed into the mitochondria and cause the release of cytochrome C; activating caspases
Which familly contains most pro- and anti-apoptotic factors?
How was Bcl-2 discovered?
Bcl-2 was identified as one half of a chromosomal translocation in B-cell lymphoma that results in Bcl-2 up-regulation and increased anti-apoptotic activity
What effect does a loss of p53 mutation have?
Mutant cells are not able to die in response to DNA damage
seen in ~50% of tumours
What initially determines the maximum size of a tumour? How is this overcome?
Diffusion limits - all cells must be ~100µm from a capillary
Can be overcome by a tumour developing a blood supply
Outline an example of the angiogenic switch
Hypoxia Induced Factor (HIF)
Under normal oxygen conditions HIF is hydroxylated (at proline and asparagine), this is recognised by Cul2 (an E3 ligase) which will target the protein for proteolysis. This hydorxylation of asparagine also blocks binding of transcriptional activators.
Under hypoxic conditions, unphosphorylated HIF is stabilised and coactivators(p300/CBP) can binf cuasing transcription of target genes.
What three factors are essential for angiogenesis?
Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factors (FGFs)
Transforming Growth Factors (TGFs)
What is the Warburg Effect?
The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
Why do cancer cells convert glucose to lactate regardless of whether oxygen is present?
Aerobic glycolysis allows diversion of glycolytic intermediates into biosynthetic pathways required for assembling new cells.
What are the emerging links between metabolism and growth control?
Proliferation signaling regulates pathways that incorporate nutrients into biomass (Eg PI3K)
Cancer-associated mutations favour these pathways and enable nutrient manufacture over efficient ATP production
How has cancer's tendency to use aerobic glycolysis been targeted for tumour treatment?
Inihibitor of PI3 kinase (Sunitinib) shown to stop glucose uptake by tumours
Shown using flourescent glucose analogue and PET scan - where tumour in liver no longer taking up the flourescent analgue after treatment with Sunitinib
Study did not show if the inhibitor was capable of stopping tumour growth and if it did extend life
What is immune surveillance?
Ability of immune system to recognise tumour cells and kill them
What factor can tumour cells use to stop natural killer proliferation?
What is immune escape?
What is immune privelage?
Ability of cancer cells to evade detection or killing
Tumours develop the ability to modulate immune function
Give an example of a type of immune escape used by cancer cells
Resistnace to Fas mediated apoptosis
- Down-regulation or mutation of Fas receptor
- Abnormalities in signal transduction proteins
- Down regulation of caspase 1, Bax or Bak
- Upregulation of Bcl2
Give an example of a type of immune privilege employed cancer cells
Cancer cells can express Fas-L and kill Fas sensitive tumour-infiltrating lymphocytes
Give an example of the search and destory capability of the immune system
Pigmentation is gradually lost around an abnormal melanocytic mole as abnormal melanocytes are destroyed. Those in surrounding area are also killed generating a distinctive halo. Likely to be happening all over the body to pre-malignant lesions that are:
i)different enough to be recognised, but
ii)not advanced enough to have acquired evasive strategies
What are the steps between normal cell divisions and immortalisation?
1) Cell divisions (~60-70 for most mammalian cells)
2) Senescence (Alive but not dividing)
3) Crisis (Cell recieving signals to divide from onocgene; usually cleads to cell death but some cells become immortal)
4) Immortalization (Cell develops ability to proliferate forever - only 1 in 107)
What is the end replication problem?
During cell division DNA polymerase can only add nucleotides onto the 3' end so the lagging template strand gets shorter
How can this problem be overcome?
Telomerase: a protein-RNA complex which can extend chromosome ends to allow replication of genome
How can this lead to immortalisation?
A mutation that causes over expression of telomerase can lead to a cell being able to divide indefinitely
This is seen in 85-90% of cancers.
What is thought to be a consequence of passage through crisis?
Altered karotypes due to random fusion and repair by non-homologous end joining