L9 Flashcards
Cancer mutations in where
Critical driver genes that cause uncontrolled proliferation
Neoplasia
New growth and the collection of cells and stroma composing new growths are referred to as neoplasms or tumours
Tumour
Tissue swelling
Benign tumour
Non-invasive but hyper-proliferative
Malignant tumour
Able to invade local tissues
Metastasise
cancer spreads via blood or lymph to colonise distant organs “called a metastasis/metastases”
leukaemias
Tumours involving blood cells are
sometimes called “liquid
tumours”
solid tumours
Tumours in tissues that form lumps
Which cells can become cancerous
Cells in any of the >100 tissue types in the body can become cancerous
Origins of cancer
- Majority of cancers are 2° to external factors → DNA damage
- Despite exposure to carcinogens, most people don’t develop overt cancer for many decades
- Cancer incidence steadily increases with age…
How Does Cancer Develop?
The body has a series of effective intrinsic defences to fight off cancer development but eventually the defence mechanisms are overcome…
Step by step
Just info
Cancer is a multi-step process
- Initiation Critical mutation in a single cell → “initiated” cell
- Promotion Initiated cell proliferates»_space; normal cells → clonal expansion → additional mutations
- Malignant conversion → irreversible mutation
- Progression → malignant cells continue to mutate
List the step processes of cancer
- Initiation
- Promotion
- Malignant conversion
- Progression
The main causes of cancer
- Tobacco smoke - >15,500 cancers/yr in Australia
- UV irradiation - >7,200/yr
- Diet/obesity - >7,000/yr
- Infections - >3,400/yr
- Alcohol - >3,200/y
Tobacco smoke causes 30% of all cancer deaths in the developed world
Carcinogens in tobacco smoke
- Contains at least 60 carcinogens
- Volatile organics - aldehydes, e.g. acrolein, formaldehyde
- Polycyclic aromatic hydrocarbons (PAH), e.g. benzo- [a]pyrene
- Tobacco specific nitrosamines, e.g. NNK heavy metals, e.g. chromium, lead
Compounds in tobacco smoke are initiators:
- Metabolic activation (PAHs/NNK) → reactive forms → DNA adducts → gene point mutations (T/C→A/G transversions i.e pyrimidines → purines)
- Smoke is also an irritant → inflammation, i.e. promoter
Tumour cells accumulate a number of mutations (capabilities) to ____ normal cellular controls on survival, proliferation and other factors
evade
Mutations occur in a limited number of key what - others are ‘passenger mutations’.
genes (’driver mutations)
Passenger mutations
mutations that do not directly drive cancer initiation and progression
6 main capabilities (halmarks for cancer)
But +2 and two enabling facotrs
- Self-sufficient in growth (+) signals
- Insensitive to growth-inhibitory (-) signals
- Can evade cell death – apoptosis
- Can proliferate indefinitely – immortalised
- Can promote blood vessel growth – angiogenesis
- Can spread away from primary tumour – invasion & metastasis
- Cellular energy deregulation
- Immune system evasion
Two enabling factors
9. Genome instability
10. Inflammation
How many mechanisms must be overcomed to produce lethal and invasive cancer
At least 8
How to cancer mutations overcome defences
Cancer mutations target one or more intrinsic control mechanisms in cells to overcome their defences
Normal cellular growth control
- Normal cells are quiescent (G0) without mitogenic (growth) signals
- Growth factors (GFs) - instruct cells to enter cell cycle (G1→S) - positive signals
- GFs act via receptors – e.g. receptor tyrosine kinases (RTKs) - convert EC → IC signal
- Growth inhibitory factors - released locally if timing is not right - negative signals stop division
quiescent: in a state or period of inactivity
Growth factor signalling
- Growth factor = ligand
- Receptor - tyrosine kinases (RTK)
- Signalling cascade
- Phosphorylation +++
- Activation of targets
Signalling can be co-opted at any step in the signal transduction pathway ->Uncontrolled proliferation
When signalling can be co-opted at any step in the signal transduction pathway what does it lead to
Uncontrolled proliferation
Inhibition of growth factor signalling will do what?
Slide 17
Any blocking will prevent transcription
Tumour cell capability 1
Self-sufficient for growth signals
- Cancer cells hv low GF dependency
- Oncogene activation will cause cells to produce their own growth signals
- For example:
- autocrine GF production (PDGF - glioblastoma),
- over-expression of GFR (EGFR - breast, stomach),
- constitutive activation of GFR (EGFR),
- constitutive activation of downstream signalling:
- Ras/Raf/MAPK proliferation pathway
- PI3K/Akt growth/survival pathway
GF=growth factor
Breach #1 - cells proliferate independently of GFs
Tumour cell Capability 2
Before Insensitivity to growth inhibition in normal cells
In normal cells not what cancer does
- Normal cells respond to anti-proliferative signals
- Regulated by tumour supressors (Anti-oncogene product)
- Brakes reg cell cycle and will force cells out & into G0 or induce cells to enter post-mitotic state with terminal differentiation to stop dividing.
Tumour cell Capability 2
Growth inhibitory signals in the cell cycle
Retinoblastoma
- TSG limit proliferation
- Prototypical TSG = Retinoblastoma (can be mutated and cause bilateral retinblastoma in children)
- Familial cancers - often due to inheritance of a mutated allele in a TSG
- The other allele mutates over time
Tumour cell Capability 2
Growth inhibitory signals in the cell cycle
Hypophosphorylated Rb
- Hypophosphorylated Rb → sequesters E2F ⊣ G1/S cell cycle progression
- CDK inhibitors (p16/INK4a) → keep Cyclin/CDKs inactive
- Growth factors → activate Cyclin/CDK complexes → phosphorylate Rb+++ → releases E2F → cell cycle progresses G1→S
- Most extracellular anti-proliferative signals (e.g. TGFβ) use the RB pathway
- Rb pathway is disrupted in most human cancersl cancers
⊣ = block
Breach #2 - cells don’t respond to growth inhibition
List all breaches
- Breach #1 - cells proliferate independently of GFs
- Breach #2 - cells don’t respond to growth inhibition
- Breach #3 - cells are resistant to apoptosis
- Breach #4 - cells are immortalised
- Breach #5 - tumours form new blood vessels
- Breach #6 - cancer cells become invasive and metastatic
- Breach #7 - cancer cells evade immune detection
Tumour cell capability 3
Evasion of cell death (apoptosis)
Normal not cancer
- TSGs suppress proliferation by either: ↓ Proliferation or↑ Apoptosis, (↑ cell loss)
- Apoptosis is regulated and causes degration, nucleus fragments and engulfed by macrophage
- Important in homeostasis -
- In humans removes finger webs
- Sensors look for abnormal cells → apoptosis
Tumour cell capability 3
Mechanisms of apoptosis evasion in tumours
- Hormone receptor (ER & AR) expression ↑ - survival signal
- Anti-apoptotic protein expression levels ↑
- B cell lymphomas often upregulate Bcl-2
- Most common pathway affected - mutations of the p53 TSG: p53 is a key DNA damage sensor - activates apoptosis in cells with severe DNA damage or metabolic problems
- Tumours - dominant negative allele (interfere with WT protein) or inactivating p53 mutations are seen in ~50% of tumours
Breach #3 - cells are resistant to apoptosis
Tumour Cell Capability 4
Cell immortalisation
Capabilities 1-3 → uncontrolled growth & proliferation but:
- Tumour cells have to inactivate hayflick mechanism → immortality
- Telomeres - mitotic “counting device” with multiple TTAGGG repeats (100-1000s)
- 50-100 bp lost/division - DNA polymerases can’t replicate 3’ ends of chromosomes
- Telomere loss → senescence &/or apoptosis
Breach #4 - cells are immortalised
(Hayflick number)
Normal cells divide a finite number of times
Telomerase
- specialised DNA polymerase
- vital for telomere maintenance
- Contains a template to transcribe 6bp telomere repeats
- expressed embryonically
How do tumours immortalise cells ?
Re-expression of telomerase is used to immortalise cells → experimental cell lines as 85-90% tumours ↑ telomerase expression
The tumour microenvironment
Capabilities 1-4 are still not enough for unlimited growth
Cancer cells need help from the microenvironment
5. O2 & nutrients - vascular network (5)
6. Invasion & spread (6)
7. Avoiding immune detection (7)
for them
Cancers coopt host cells in microenvironment to do this work
Tumour cell capability 5
New blood vessels (angiogenesis)
Normal and tumours
- Cells need nutrients and O2 and to remove waste
- > 100μM from blood vessel → risk of necrosis
- Tumours lack the ability to promote angiogenesis initially but it is triggered surprisingly early
- Tumours “flick the angiogenic switch” to keep growing larger
Breach #5 - tumours form new blood vessels
Tumour cell capability 5
Angiogenesis and tumour progression
- Angiogenesis/neovascularisation - complex process
- Involves many +’ve and –’ve signals:
– positive - e.g. vascular endothelial GF (VEGF)
– negative - e.g. thrombospondin-1 (Tsp) - Shift in the balance of signalling proteins (VEGF↑, Tsp-1↓) → angiogenesis
- Tumour cells and stromal cells affect balance
Breach #5 - tumours form new blood vessels
Tumour cell capability 6
Tissue invasion and distant metastasis
Cancer and where it spreads colorectal, breast and prostate
- Cancer death due to spread of tumours to distant sites
- Like in:
– colorectal cancer(CRC) → liver (portal circulation)
– Breast cancer → bone, lungs, liver & brain
– Prostate cancer → bone
Breach #6 - cancer cells become invasive and metastatic
Tumour cell capability 7
Evasion of the immune system
- The immune system is a barrier to tumour progression
- The immune system patrols tissues and routinely eliminates the vast majority of abnormal cells
- Tumours evade the immune system
- They co-opt immune cells to ↑growth & encourage invasion: TAMs * Tregs * iDCs etc
Breach #7 - cancer cells evade immune detection
