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PHAR2220 > L9 > Flashcards

L9 Flashcards

1
Q

Cancer mutations in where

A

Critical driver genes that cause uncontrolled proliferation

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2
Q

Neoplasia

A

New growth and the collection of cells and stroma composing new growths are referred to as neoplasms or tumours

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3
Q

Tumour

A

Tissue swelling

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4
Q

Benign tumour

A

Non-invasive but hyper-proliferative

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5
Q

Malignant tumour

A

Able to invade local tissues

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6
Q

Metastasise

A

cancer spreads via blood or lymph to colonise distant organs “called a metastasis/metastases”

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7
Q

leukaemias

A

Tumours involving blood cells are
sometimes called “liquid
tumours”

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8
Q

solid tumours

A

Tumours in tissues that form lumps

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9
Q

Which cells can become cancerous

A

Cells in any of the >100 tissue types in the body can become cancerous

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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…
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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

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12
Q

Cancer is a multi-step process

A
  • Initiation Critical mutation in a single cell → “initiated” cell
  • Promotion Initiated cell proliferates&raquo_space; normal cells → clonal expansion → additional mutations
  • Malignant conversion → irreversible mutation
  • Progression → malignant cells continue to mutate
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13
Q

List the step processes of cancer

A
  1. Initiation
  2. Promotion
  3. Malignant conversion
  4. Progression
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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

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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
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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
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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
  1. Self-sufficient in growth (+) signals
  2. Insensitive to growth-inhibitory (-) signals
  3. Can evade cell death – apoptosis
  4. Can proliferate indefinitely – immortalised
  5. Can promote blood vessel growth – angiogenesis
  6. Can spread away from primary tumour – invasion & metastasis
  7. Cellular energy deregulation
  8. 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
  1. Growth factor = ligand
  2. Receptor - tyrosine kinases (RTK)
  3. Signalling cascade
  4. Phosphorylation +++
  5. Activation of targets

Signalling can be co-opted at any step in the signal transduction pathway ->Uncontrolled proliferation

25
Q

When signalling can be co-opted at any step in the signal transduction pathway what does it lead to

A

Uncontrolled proliferation

26
Q

Inhibition of growth factor signalling will do what?

Slide 17

A

Any blocking will prevent transcription

27
Q

Tumour cell capability 1

Self-sufficient for growth signals

A
  • 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

28
Q

Tumour cell Capability 2

Before Insensitivity to growth inhibition in normal cells

In normal cells not what cancer does

A
  • 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
Q

Tumour cell Capability 2

Growth inhibitory signals in the cell cycle

Retinoblastoma

A
  • 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
Q

Tumour cell Capability 2

Growth inhibitory signals in the cell cycle

Hypophosphorylated Rb

A
  • 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

30
Q

List all breaches

A
  • 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
Q

Tumour cell capability 3

Evasion of cell death (apoptosis)

Normal not cancer

A
  • 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
Q

Tumour cell capability 3

Mechanisms of apoptosis evasion in tumours

A
  • 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
Q

Tumour Cell Capability 4

Cell immortalisation

Capabilities 1-3 → uncontrolled growth & proliferation but:

A
  • 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
Q

(Hayflick number)

A

Normal cells divide a finite number of times

35
Q

Telomerase

A
  • specialised DNA polymerase
  • vital for telomere maintenance
  • Contains a template to transcribe 6bp telomere repeats
  • expressed embryonically
36
Q

How do tumours immortalise cells ?

A

Re-expression of telomerase is used to immortalise cells → experimental cell lines as 85-90% tumours ↑ telomerase expression

37
Q

The tumour microenvironment

Capabilities 1-4 are still not enough for unlimited growth

A

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
Q

Tumour cell capability 5

New blood vessels (angiogenesis)

Normal and tumours

A
  • 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
Q

Tumour cell capability 5

Angiogenesis and tumour progression

A
  • 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
Q

Tumour cell capability 6

Tissue invasion and distant metastasis

Cancer and where it spreads colorectal, breast and prostate

A
  • 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
Q

Tumour cell capability 7

Evasion of the immune system

A
  • 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

PHAR2220 (20 decks)

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