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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 that is dependent on shear stress and external factors like macrophages

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2
Q

What is the main trigger for angiogenesis?

A

Hypoxia

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3
Q

What is the most essential pro-angiogenic factor?

A

VEGF (Vascular Endothelial Growth Factor)

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4
Q

State the 5 steps describing the process of sprouting angiogenesis

A
  1. Endothelial activation => tip/stalk cell selection
  2. Tip cell navigation and stalk cell proliferation
  3. Branching coordination
  4. Stalk elongation, tip cell fusion, and lumen formation
  5. Perfusion and vessel maturation.
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5
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, Von Hippel Lindau protein (encoded by a tumour suppressor gene) binds to HIF-α => hydroxyproline and ubiquitin attachment => degredation by proteasome => NO ANGIOGENESIS
  • In hypoxic conditions, HIF-α doesn’t bind to von Hippel Lindau so it can associate with HIF-β => expression of genes (e.g. VEGF) => ANGIOGENESIS
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6
Q

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

A

5

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

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7
Q

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

A

3
VEGFR 1, 2 and 3

Note: VEGFR3 has disulphide bridge in its ligand binding domain

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8
Q

How many coreceptors are there for VEGF? List them.

A

2

Neuropilin 1 and 2 (Nrp 1/2)

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9
Q

Which receptor is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival, proliferation.

A

VEGFR2

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10
Q

What pathway is crucial for the selection of tip cells?

A

Canonical Notch signalling pathway between adjacent endothelial cells at the angiogenic front

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11
Q

Describe the notch signalling pathway

A
  • Notch receptors and ligands are membrane-bound proteins that interact through their extracellular domains.
  • This interaction triggers a series of proteolytic cleavages of the Notch receptor
  • The final one, catalysed by the g-secretase complex, releases the active Notch intercellular domain (NICD) from the cell membrane
  • NICD translocates to the nucleus and binds to the transcription factor RBP-J => inhibition of expression of VEGF receptors in the cell
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12
Q

What is another name for the notch ligand?

A

Delta-like ligand (Dll4)

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13
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
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
The tip cells are those cells which receive the ‘highest dose’ of VEGF and so responds by migrating according to the VEGF gradient

Note that initially, Dll4 and Notch signaling are thought to be balanced between adjacent endothelial cells until presumptive tip cells eventually increase Dll4 expression

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14
Q

After appropriate stimulation, what else is required for tip cell formation?

A

Tip-cell formation requires degradation of the basement membrane, pericyte detachment and loosening of endothelial cell junctions

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15
Q

State how the tip cells are able to navigate and migrate

A

Tip cells navigate in response to guidance signals (such as semaphorins and ephrins) and adhere to the extracellular matrix (mediated by integrins) to migrate.

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16
Q

How do proliferating stalk cells become stabilised?

A

Proliferating stalk cells attract pericytes and deposit basement membranes to become stabilized

17
Q

State the recruited immune cells involved in the angiogenic process and state their role

A

Recruited myeloid cells such as tumour-associated macrophages (TAMs) and TIE-2-expressing monocytes (TEMs) associated with tip cells can produce pro-angiogenic factors or proteolytically liberate angiogenic growth factors from the ECM.
Macrophages carve out tunnels in the extra cellular matrix (ECM), providing avenues for capillary infiltration.

18
Q

Describe the stabilisation and quiescence after fusion of neighbouring branches

A

Lumen formation allows perfusion of the neovessel, which resumes quiescence by promoting a phalanx phenotype, re-establishment of junctions, deposition of basement membrane, maturation of pericytes and production of vascular maintenance signals.

19
Q

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

A

VE-Cadherin (Constitutively expressed at junctions)

  • Controls contact inhibition of cell growth
  • Promotes survival of EC
20
Q

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

A

Angiopoietin 1 (Ang-1)

21
Q

How does Ang-1 carry out its function?

A

Ang-1 is constitutively released by pericytes and binds to Tie-2 receptors almost exclusively expressed by endothelial cells.
=> Promotes vessel stability and inhibits inflammatory gene expression

22
Q

Where is Angiopoietin 2 released from and what triggers its release? How does it affect Ang-1 signalling?

A

Ang-2 is stored in Weibel–Palade bodies (in endothelial cells) and is rapidly secreted upon inflammatory stimulus.
=> Antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis

23
Q

State three diseases in which Ang-2 plasma levels are raised

A

Congestive heart failure
Sepsis
Chronic Kidney Disease

24
Q

How do tumours less than 1mm^3 receive oxygen and nutrients? How do larger tumours overcome this problem?

A

Receive oxygen and nutrients by diffusion from host vasculature.
Larger tumors require new vessel network so secrete angiogenic factors

25
Q

What is the name given to the point at which a tumour begins to initiate signals to generate new vasculature? What does its timing in the tumour-progression pathway depend on? What does the switch begin with?

A

Angiogenic switch

It can occur at different stages in the tumour-progression pathway, depending on the nature of the tumour and its microenvironment.

The switch begins with perivascular detachment and vessel dilation

26
Q

What are some of the characteristics of tumour blood vessels?

A
  • Irregularly shaped, dilated, tortuous
  • Not organised into definitive venules, arterioles and capillaries
  • Leaky and haemorrhagic, partly due to the overproduction of VEGF
  • Perivascular cells often become loosely associated

Note that pericytes loosely associated with tumour-associated blood vessels favours chronic leakage in tumours; this is enhanced by angiopoietin 2.

27
Q

What do Cancer-associated fibroblasts (CAFs) do to promote tumour angiogenesis? Where do they come from?

A

Under the influence of transforming growth factor-β (TGFβ) and other tumour-derived factors, peri-tumoural fibroblasts differentiate into CAFs
=> They secrete extracellular matrix and pro-angiogenic growth factors

28
Q

Describe the role of platelets in tumour angiogenesis

A

Tumours cause platelet activation, aggregation and degranulation;
Activated platelets release pro-angiogenic mediators and proteases that support the proliferation and activation of CAFs, such as PDGFB and TGFβ
Also, angiostatic molecules: thrombospondin 1, plasminogen activator inhibitor 1 (PAI1), endostatin

29
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

30
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 chemotherapeutic drugs

31
Q

What is avastin?

A

Anti-VEGF humanised mouse antibody

Also called bevacizumab

32
Q

What are the side effects of avastin?

A 
GI perforation 
Hypertension 
Proteinuria 
Venous thrombosis 
Haemorrhage
33
Q

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

A

Tumour adopts evasive strategy to bypass the angiogenic blockade

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

34
Q

What did avastin start getting used for other than cancer?

A

Diabetic retinopathy

Age-related macular degeneration (AMD); Abnormal growth of choroidal blood vessels => “Leaky” vessels cause oedema => Visual impairment

35
Q

What slightly modified form of avastin became licensed by the FDA to treat AMD?

A

Lucentis (ranibizumab)

But Avastin is much cheaper

36
Q

What can pro-angiogenic therapies potentially be used for?

A

Ischaemic diseases; MI, peripheral ischaemic disease

Cancer (15 decks)

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