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YR2: MCD Cancer > 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, dependent on shear stress + 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 (hypoxia-inducible factor) is a TF responsible for expression of genes involved in angiogenesis
In normoxic conditions, HIF is bound to von Hippel Lindau protein (tumour suppressor), which inhibits HIF from promoting angiogenesis
In hypoxic conditions, HIF detaches so can go into nucleus, bind DNA + drive expression of genes involved in angiogenesis

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5
Q

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

A

5
VEGF-A, B, C, D
PlGF (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 + 3

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7
Q

How many coreceptors are there for VEGF? List them.

A

2

Neuropilin (Nrp) 1 + 2

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8
Q

Which receptor is the major mediator in VEGF-dependent angiogenesis? What does it do?

A

VEGFR2

Activates signalling pathways that regulate endothelial cell migration, survival + proliferation

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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 domain in the stalk cell is cleaved

This translocates to the nucleus, binds to RBP-J + 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

VEGF activation increases expression of Dll4 on the tip cell
Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
Dll4 expressing tip cells develop a motile, invasive + sprouting phenotype
Adjacent stalk cells form the base of the emerging sprout + proliferate to support sprout elongation

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13
Q

How do macrophages participate in angiogenesis?

A

Carve out tunnels in ECM providing avenues for capillary infiltration
Tissue resident macrophages can be associated with angiogenic tip cells during anastomosis

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14
Q

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

A

Pericytes

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15
Q

Which cell adhesion molecules are essential for vessel stabilisation and quiescence? What else do they do?

A

VE-Cadherins (homophillic interaction)
Control contact inhibition of cell growth
Promotes survival of cell

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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

Promotes vessel stability

Inhibits inflammatory gene expression

19
Q

Describe the actions of angiopoietin 2.

A

Ang 2 antagonises Ang 1 signalling
Promotes vascular instability
Promotes VEGF dependent angiogenesis

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 malformed because the signals are not physiological
Vessels can be irregularly shaped, distended, disorganised, tortuous, leaky + 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 + improve efficiency of drug delivery

23
Q

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

A

Can make tumour blood supply inadequate for delivery of drugs

24
Q

What is avastin?

A

Anti-VEGF humanised mouse antibody

25
Q

What are 6 side effects of avastin?

A 
GI perforation  
Hypertension 
Proteinuria 
Venous thrombosis  
Haemorrhage
Wound healing complications
26
Q

What are the 3 main mechanisms of resistance to VEGF blockade?

A

VEGF inhibition aggravates hypoxia increasing tumour’s production of other angiogenic factors/ increases tumour invasiveness
Tumour vessel cells may be less sensitive to VEGF inhibition
Tumour cells that recruit pericytes may be less responsive to VEGF inhibition

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

List 3 physiological circumstances angiogenesis occurs in

A

Development
Menstrual cycle
Wound healing

30
Q

List 5 pathological circumstances angiogenesis occurs in

A 
Cancer
Chronic inflammatory diseases
Retinopathies
Ischemic diseases 
Vascular malformations
31
Q

Briefly describe the step by step sprouting angiogenesis process

A

Hypoxia stimulates angiogenic factor release
VEGF binds to a receptor on a cell which becomes the Tip cell
Cells adjacent become support “stalk cells” + proliferate
Stalk elongation, tip cell fusion + lumen formation occur
Then there is perfusion + vessel maturation

32
Q

When is Ang 2 released?

A

When the endothelium is activated e.g. in inflammation

33
Q

How are platelets involved in tumour angiogenesis?

A

Activated platelets are a source of pro-angiogenic + angiostatic factors
Tumours cause platelet activation, aggregation + degranulation
Overall they are pro-angiogenic

34
Q

Describe the limited efficacy of Avastin

A

No overall survival advantage over chemo alone

Sometime transitory benefit, then restoration of tumour growth + progression

35
Q

How may tumours become independent of VEGF for a blood supply?

A

Vascular mimicry
Tumour cells organise themselves to form vessel like channels + allow blood to circulate
Thus blocking VEGF will not be effective in stopping blood supply

36
Q

What is AMD?

A

Age-related macular degeneration
Abnormal growth of choroidal blood vessels
Leaky vessels cause oedema + visual impairment

37
Q

What new technique is being tested for cancer drug screening?

A

“tumour on a chip” in vitro models incorporating tumour cells + vasculature

38
Q

In which circumstances would pro-angiogenic therapy be useful?

A

Myocardial infarction

Peripheral ischaemia

YR2: MCD Cancer (18 decks)

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