Cancer Y2 > Angiogenesis > Flashcards

Angiogenesis Flashcards

(48 cards)

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1
Q

Examples of when angiogenesis occurs

A

embryonic development, wound healing, menstrual cycle

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2
Q

Insufficient angiogenesis example (4)

A

Baldness

  • MI- ischaemia
  • Limb fractures
  • Thrombosis
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3
Q

Excessive angiogenesis examples (4)

A
  • Retinal disease
  • Cancers
  • Atherosclerosis
  • Obesity
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4
Q

3 ways to make a blood vessel

A
  1. Vasculogenesis (bone marrow progenitor cells)
  2. Angiogenesis (sprouting-> Sprouts from a pre-existing blood vessel)
  3. Arteriogenesis (collateral growth)
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5
Q

Describe the model of sprouting angiogenesis starting with a pro-angiogenic stimulus

A
  • A pro-angiogenic stimulus (e.g. a growth factor) triggers the activation of specific endothelial cells
  • These endothelial cells’ cytoskeletons change polarity in order to put out ‘fingers’ to sense its external environment
  • The cell also has to remain in contact with the other endothelial cells This means it needs to communicate with them at the endothelial cell-cell contacts, to cause them to divide while the original cell (the TIP cell) migrates towards to the stimulus
  • Eventually, the sprout fuses with another sprout coming from somewhere else
  • This new blood vessel then needs stabilizing to avoid vascular malformations
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6
Q

What size blood vessels can undergo sprouting angiogenesis?

A

Small

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7
Q

What condition triggers angiogenesis

A

Hypoxia

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8
Q

What protein controls gene expression by oxygen

A
  • Hypoxia-inducible transcription factor (HIF-alpha)
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9
Q

What binds HIF-alpha in oxygenated conditions

A

a protein called Von Hippel-Lindau

a tumour suppressor gene known as pVHL

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10
Q

What does protein called Von Hippel-Lindau do

A

Binds to HIF-alpha in oxygenated conditions causing ubiquination (breakdown) of the molecule

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11
Q

What happens to HIF-alpha when there is lack of oxygen

A

it is not bound by VHL and so enters the nucleus and binds HIF-beta, which drives transcription of genes that promote angiogenesis such as VEGF

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12
Q

example of gene that promotes angiogenesis?

A

VEGF

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13
Q

what’re the 5 VEG factors

A

a b c d and PIGF (placental growth factor)

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14
Q

what does VEGF stand for

A

VASCULAR ENDOTHELIAL GROWTH FACTOR

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15
Q

What type of receptor is the VEGFR

A

tyrosine kinase (combine to form dimers)

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16
Q

What’re the VEGF coreceptors

A

Nrp1 and Nrp2

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17
Q

What’re the VEGR

A

1 2 and 3

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18
Q

which VEGFR is the major mediator of VEGF-dependent angiogenesis

A

VEGFR2

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19
Q

What is tip cells selection based off

A

Notch signaling between adjacent endothelial cells at the angiogenic front

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20
Q

what guides the direction of a tip cell sprout

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A

VEGF gradient

21
Q

What do Notch receptors do

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A

signal for tip cells selection

22
Q

The X of Notch (NICD) translocates to the nucleus and binds to the transcription factor Y

Study These Flashcards
A 
X = intracellular domain
Y = RBP-J
23
Q

Describe the process of tip cell selection starting with VEGF activation

Study These Flashcards
A
  1. VEGF activation increases expression of Dll4
  2. Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
  3. Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
  4. Adjacent cells (Stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation
24
Q

What helps blood vessel stabilisation

Study These Flashcards
A

pericytes need to be wrapped around etc

25
What protein expressed in adherens junctions is important for adhesion and contact inhibition
Cadherin
26
What are key mural cells
Pericytes
27
What do pericytes do (2)
- They wrap around new capillaries to help to stabilize them | - They produce a growth factor called angiopoietin-1
28
What type of cell is a pericyte
Mural cell
29
Ang-1 and Ang-2 are antagonistic ligands of the X receptor
X = Tie2
30
What produces Angiopoietin 1
Pericytes
31
What does Ang1 do
binds to Tie2 to promote vessel stability and inhibits inflammatory gene expression
32
What does Ang2 do
antagonises Ang-1 signalling, promoting vascular instability and VEGF-dependent angiogenesis
33
What conditions have raised Ang 2 levels
congestive HF, sepsis and CKD
34
Tumours less than 1 mm3 receive oxygen and nutrients ....
by diffusion from host vasculature
35
Tumours larger than 1mm3 require X for oxygen and nutrients
X = new vessel network
36
How big does a tumour have to be before it needs its own vessel network
Larger than 1mm3
37
What is the angiogenic switch in tumour formation
It is the point at which the tumour becomes dependent on angiogenesis for growth
38
the point at which the tumour becomes dependent on angiogenesis for growth is known as...
The angiogenic switch
39
Describe tumour blood vessels (5)
- Irregularly shaped, dilated, tortuous - Not organized into definitive venules, arterioles and capillaries - Leaky and haemorrhagic, partly due to excessive VEGF - Perivascular cells are often loosely associated - Some tumours may recruit endothelial progenitor cells from the bone marrow
40
Agents targeting the VEGF pathway to treat tumours?
1. ANTI-VEGF ANTIBODIES 2. SOLUBLE VEGF RECEPTORS 3. ANTI-VEGFR ANTIBODIES 4. SMALL MOLECULE VEGFR INHIBITORS
41
Example of ANTI-VEGF ANTIBODIES
bevacizumab (Avastin)
42
Side effects of ANTI-VEGF ANTIBODIES (6)
```  GI perforation  Hypertension  Proteinuria  Venous thrombosis  Haemorrhage  Wound healing complications ```
43
effectiveness of ANTI-VEGF ANTIBODIES
- No overall survival advantage over chemo alone | - No quality-of-life or survival advantage
44
2 types of cancer resistance to angio-VEGF treatment?
1. Evasive resistance- an adaptation to circumvent the specific angiogenic blockade 2. Intrinsic or pre-existing indifference (e.g. the tumour is not really dependent on VEGF in the first place)
45
What is vasculogenic mimicry
Basically the cancer cells pretend to be blood vessel cells to avoid anti-cancer therapies
46
Other diseases angiogenic therapies can be used for? (2)
- Anti-angiogenic therapies for abnormal retina vascularization (diabetic retinopathy, wet AMD) - Pro-angiogenic therapies for ischemic diseases (myocardial infarction, peripheral ischaemic disease)
47
What is age-related macular degeneration
Abnormal growth of choroidal blood vessels - ‘Leaky’ vessels cause oedema - Visual impairment
48
What is Vascular permeability factor also known as
VEGF
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