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Y2 Cancer (MCD) > 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

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

In normoxic conditions, HIF-alpha is bound to von Hippel Lindau protein (tumour suppressor) and hydroxyproline, which inhibits HIF from promoting angiogenesis

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

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5
Q

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

A

5
VEGF-A, B, C, D
PIGF (placental growth factor)

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6
Q

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

A

3

VEGFR 1, 2 and 3

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7
Q

How many coreceptors are there for VEGF? List them.

A 
2 
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

How does Notch signalling work?

A

One cell has the notch ligand (DII4) which binds to the other cell’s notch receptor

The intracellular domain of the notch receptor (NICD domain) is cleaved

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

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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

In the context of sprouting angiogensis, what effect does VEGF have on notch signalling?

A

VEGF increases expression of Dll4 in one endothelial cell before the others. This cell becomes the tip cell.

Dll4 then drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell

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

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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

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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

Angiopoietin-Tie2 signalling pathway

18
Q

Describe the actions of angiopoietin 1.

A

Ang 1 promotes quiescence in the blood vessel

19
Q

Describe the actions of angiopoietin 2.

A

Ang 2 is an antagonist and gets released when you need to form a new vessel or when you need to respond to inflammation or the 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 - partly due to excess VEGF

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 as there are many other factors promoting angiogenesis

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?

A

Lucentis (ranibizumab)

29
Q

What initiates sprouting angiogenesis?

A

Cell hypoxia stimulates VEGF production

VEGF creates a gradient through the ECM to blood vessels

VEGF activates a tip cell through the notch selection process

Tip cell and supporting stalk cells follow the VEGF gradient to the hypoxic cell.

30
Q

How does sprout outgrowth and guidence work?

A

Initiation and tip cell selection

Tip cell navigation

Stalk elongation

31
Q

How does vessel stabilisation work?

A

Perfusion and oxygenation

Maturation and stabilisation

32
Q

What are the 2 ways to supply a tumour?

A

Angiogenesis:
tumours produce factors to promote vessel growth into the tumour mass

Vasculogenic mimicry:
Tumour cells organise themselves to form vessellike channels, causing vessels to hook up to channels within the tumour mass.

33
Q

What is the “tumour on a chip” platform?

A

A microphysiological system that incorporates human cells in a 3D ECM supported by human microvessels

Used to better assess the effectiveness of drugs

34
Q

What are the applications of anti-angiogenic therapy?

A

Cancer

Diabetic retinopathy

Age-related macular degeneration (AMD)

35
Q

What are the applications of pro-angiogenic therapy

A

Promote neo-vascularisation to prevent ischemic damage in myocardial ischemia and DVT

Y2 Cancer (MCD) (16 decks)

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