L9 Flashcards
(42 cards)
1
Q
Cancer mutations in where
A
Critical driver genes that cause uncontrolled proliferation
2
Q
Neoplasia
A
New growth and the collection of cells and stroma composing new growths are referred to as neoplasms or tumours
3
Q
Tumour
A
Tissue swelling
4
Q
Benign tumour
A
Non-invasive but hyper-proliferative
5
Q
Malignant tumour
A
Able to invade local tissues
6
Q
Metastasise
A
cancer spreads via blood or lymph to colonise distant organs “called a metastasis/metastases”
7
Q
leukaemias
A
Tumours involving blood cells are
sometimes called “liquid
tumours”
8
Q
solid tumours
A
Tumours in tissues that form lumps
9
Q
Which cells can become cancerous
A
Cells in any of the >100 tissue types in the body can become cancerous
10
Q
Origins of cancer
A
- 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…
11
Q
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…
A
Step by step
Just info
12
Q
Cancer is a multi-step process
A
- 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
13
Q
List the step processes of cancer
A
- Initiation
- Promotion
- Malignant conversion
- Progression
14
Q
The main causes of cancer
A
- 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
15
Q
Carcinogens in tobacco smoke
A
- 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
16
Q
Compounds in tobacco smoke are initiators:
A
- 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
17
Q
Tumour cells accumulate a number of mutations (capabilities) to ____ normal cellular controls on survival, proliferation and other factors
A
evade
18
Q
Mutations occur in a limited number of key what - others are ‘passenger mutations’.
A
genes (’driver mutations)
19
Q
Passenger mutations
A
mutations that do not directly drive cancer initiation and progression
20
Q
6 main capabilities (halmarks for cancer)
But +2 and two enabling facotrs
A
- 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
21
Q
How many mechanisms must be overcomed to produce lethal and invasive cancer
A
At least 8
22
Q
How to cancer mutations overcome defences
A
Cancer mutations target one or more intrinsic control mechanisms in cells to overcome their defences
23
Q
Normal cellular growth control
A
- 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
24
Q
Growth factor signalling
A
- 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
25
When signalling can be co-opted at any step in the signal transduction pathway what does it lead to
Uncontrolled proliferation
26
Inhibition of growth factor signalling will do what?
| Slide 17
Any blocking will prevent transcription
27
# 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
## Footnote
Breach #1 - cells proliferate independently of GFs
28
# 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.
28
# 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
29
# 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
## Footnote
Breach #2 - cells don’t respond to growth inhibition
30
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
31
# 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
32
# 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
33
# 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
34
(Hayflick number)
Normal cells divide a finite number of times
35
Telomerase
* specialised DNA polymerase
* vital for telomere maintenance
* Contains a template to transcribe 6bp telomere repeats
* expressed embryonically
36
How do tumours immortalise cells ?
Re-expression of telomerase is used to immortalise cells → experimental cell lines as 85-90% tumours ↑ telomerase expression
37
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
38
# 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
39
# 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
40
# 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
41
# 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
