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CANKER - OBG > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

What are the three ways of making blood vessels?

A

Vasculogenesis – formation of new blood vessels from bone marrow progenitor cells

Angiogensis – formation of new blood vessels by sprouting from pre-existing vessels

Arteriogenesis – collateral growth of blood vessels that is dependent on shear stress and external factors like macrophages (to accommodate occlusions)

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2
Q

What is the main signal for angiogenesis?

A

Hypoxia

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3
Q

What is the most important pro-angiogenic factor?

A

VEGF (Vascular Endothelial Growth Factor)

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4
Q

Explain the mechanism by which hypoxia triggers angiogenesis.

A

HIF (hypoxia-inducible factor) is a transcription factor that is responsible for the expression of genes involved in angiogenesis

In normoxic conditions, HIF is bound to von Hippel Lindau protein (pVHL) (tumour suppressor), which inhibits HIF from promoting angiogenesis – degraded by proteasome

In hypoxic conditions, HIF is not bound to von Hippel Lindau so it can regulate transcription and express genes involved in angiogenesis

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5
Q

How many members are there in the VEGF family? List them.

A

5 families:

VEGF-A, B, C, D and PIGF (placental growth factor)

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6
Q

How many tyrosine kinase receptors are there for VEGF? List them.

A

3 TK receptors

VEGFR 1, 2 and 3

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7
Q

How many coreceptors are there for VEGF? List them.

A 
2 co-receptors
Neuropilin 1 (Nrp 1) and 2
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8
Q

Which receptor is the major mediator in VEGF-dependent angiogenesis?

A

VEGFR2

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9
Q

What pathway is crucial for the selection of tip cells?

A

Notch signalling

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10
Q

What happens when the notch ligand binds to the notch receptor?

A

The intracellular NICD domain is cleaved

This then translocates to the nucleus and binds to the transcription factor RBP-J and regulates transcription

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11
Q

What is another name for the notch ligand?

A

Delta-like ligand (Dll4)

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12
Q

What effect does VEGF have on notch signalling?

A

It increases expression of Dll4

Dll4 then drives Notch signalling , which inhibits expression of VEGFR2 in the adjacent cell (stalk cells)

Dll4 expressing tip cells develop a motile, invasive and sprouting phenotype

Adjacent stalk cells form the base of the emerging sprout and proliferate to support sprout elongation

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13
Q

Which cell type is involved in vessel anastomosis and helping stabilise newly formed vessels by promoting tip cell fusion?

A

Macrophages- Macrophages carve out tunnels in the ECM for subsequent capillary infiltration

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14
Q

Which other cell type is recruited to help with the stabilisation ofthe newly formed vessel?

A

Pericytes

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15
Q

Which cell adhesion molecules are essential for vessel stabilisation and quiescence?

A

VE-Cadherin (and Ang-1):
oConstitutively expressed at junctions.
oControls contact inhibition of cell growth.
oPromotes the survival of the EC

Barrier formation facilitates the stabilisation of the vessel

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16
Q

What growth factor do pericytes produce that is important for stabilisation of new blood vessels?

A

Angiopoietin 1

17
Q

Which important signalling pathway modulates the activation and return to quiescence of endothelial cells?

A

Angiopoietin1-Tie2 signalling pathway (Ang/tie2)

Ang1 binds Tie2 in endothelia- promotes quiescence

18
Q

Describe the actions of angiopoietin 1.

A

Ang 1 promotes quiescence in the blood vessel, also inhibits inflammatory response

19
Q

Describe the actions of angiopoietin 2.

A

Ang 2 is an antagonist of Ang 1 and gets released when you need to form a new vessel or when you need to respond to inflammation/vasculature needs to be destabilised

20
Q

What is the name given to the point at which a tumour begins to initiate signals to generate new vasculature?

A

Angiogenic switch

21
Q

What are some of the issues with tumour blood vessels?

A

They are not properly formed because the signals are not physiological

Vessels can be irregularly shaped, distended, tortuous
Leaky and haemorrhagic etc

Haemorrhage is common in tumours.

22
Q

What is the aim of anti-angiogenic therapy in cancer?

A

To normalise tumour blood vessels to reduce hypoxia and improve efficiency of drug delivery

23
Q

What are the consequences of being too aggressive with anti-angiogenic therapy?

A

This can make the tumour blood supply inadequate for the delivery of drugs

24
Q

What is avastin?

A

Anti-VEGF humanised mouse antibody

Also called bevacizumab

25
Q

What are the side effects of avastin?

A

GI perforation

Hypertension

Proteinuria

Venous thrombosis

Haemorrhage

26
Q

What are the two main methods of unconventional resistance to VEGF blockade?

A

Tumour adopts evasive strategy – adapts to bypass the angiogenic blockade

Intrinsic or pre-existing difference – a tumour may not have been particularly sensitive to VEGF in the first place

27
Q

What did avastin start getting used for other than cancer?

A

Age-related macular degeneration (AMD)

28
Q

What slightly modified form of avastin became licensed by the FDA to treat AMD? (Age-related macular degeneration )

A

Lucentis (ranibizumab)

29
Q

what does stabilisation of new vessels involve

A
  • Reforming endothelial monolayer
  • Recruiting pericytes
  • Switching off active angiogenesis process
30
Q

what makes up mural cells

A

Mural cells = VSMCs and pericytes

31
Q

what are the other methods of resistance to anti-angiogenic factors (anti-VEGF)

A
  1. VEGF inhibition leads to more hypoxia–> more pro-angiogenic factors released to compensate/ more invasiveness
  2. May be less sensitive to VEGF due to tumour cells lining the vessels
  3. tumours that recruit pericytes may be less responsive
  4. Tumour cell Vascular Mimicry: the tumour cells remodel themselves to look like vessels so that when pressed by a single vessel this is enough to provide nutrient support
32
Q

what would pro-angiogenic therapies be used for

A

MI, peripheral ischemic disease

CANKER - OBG (14 decks)

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