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Cancer Y2 > Angiogenesis > Flashcards

Angiogenesis Flashcards

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

A

VEGF gradient

21
Q

What do Notch receptors do

A

signal for tip cells selection

22
Q

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

A 
X = intracellular domain
Y = RBP-J
23
Q

Describe the process of tip cell selection starting with VEGF activation

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

A

pericytes need to be wrapped around etc

25
Q

What protein expressed in adherens junctions is important for adhesion and contact inhibition

A

Cadherin

26
Q

What are key mural cells

A

Pericytes

27
Q

What do pericytes do (2)

A
  • They wrap around new capillaries to help to stabilize them

- They produce a growth factor called angiopoietin-1

28
Q

What type of cell is a pericyte

A

Mural cell

29
Q

Ang-1 and Ang-2 are antagonistic ligands of the X receptor

A

X = Tie2

30
Q

What produces Angiopoietin 1

A

Pericytes

31
Q

What does Ang1 do

A

binds to Tie2 to promote vessel stability and inhibits inflammatory gene expression

32
Q

What does Ang2 do

A

antagonises Ang-1 signalling, promoting vascular instability and VEGF-dependent angiogenesis

33
Q

What conditions have raised Ang 2 levels

A

congestive HF, sepsis and CKD

34
Q

Tumours less than 1 mm3 receive oxygen and nutrients ….

A

by diffusion from host vasculature

35
Q

Tumours larger than 1mm3 require X for oxygen and nutrients

A

X = new vessel network

36
Q

How big does a tumour have to be before it needs its own vessel network

A

Larger than 1mm3

37
Q

What is the angiogenic switch in tumour formation

A

It is the point at which the tumour becomes dependent on angiogenesis for growth

38
Q

the point at which the tumour becomes dependent on angiogenesis for growth is known as…

A

The angiogenic switch

39
Q

Describe tumour blood vessels (5)

A
  • 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
Q

Agents targeting the VEGF pathway to treat tumours?

A
  1. ANTI-VEGF ANTIBODIES
  2. SOLUBLE VEGF RECEPTORS
  3. ANTI-VEGFR ANTIBODIES
  4. SMALL MOLECULE VEGFR INHIBITORS
41
Q

Example of ANTI-VEGF ANTIBODIES

A

bevacizumab (Avastin)

42
Q

Side effects of ANTI-VEGF ANTIBODIES (6)

A 
 GI perforation
 Hypertension
 Proteinuria
 Venous thrombosis
 Haemorrhage
 Wound healing complications
43
Q

effectiveness of ANTI-VEGF ANTIBODIES

A
  • No overall survival advantage over chemo alone

- No quality-of-life or survival advantage

44
Q

2 types of cancer resistance to angio-VEGF treatment?

A
  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
Q

What is vasculogenic mimicry

A

Basically the cancer cells pretend to be blood vessel cells to avoid anti-cancer therapies

46
Q

Other diseases angiogenic therapies can be used for? (2)

A
  • Anti-angiogenic therapies for abnormal retina vascularization (diabetic retinopathy, wet AMD)
  • Pro-angiogenic therapies for ischemic diseases (myocardial infarction, peripheral ischaemic disease)
47
Q

What is age-related macular degeneration

A

Abnormal growth of choroidal blood vessels

  • ‘Leaky’ vessels cause oedema
  • Visual impairment
48
Q

What is Vascular permeability factor also known as

A

VEGF

Cancer Y2 (15 decks)

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