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Y2 Cancer > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

What is the physiology of angiogenesis

A

Development
Menstrual Cycle
Wound Healing

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2
Q

What is the pathology of angiogenesis

A 
Cancer
Chronic inflammatory diseases
Retinopathies
Ischemic diseases
Vascular malformations
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3
Q

Give examples of growth factors that are involved in activating angiogenesis

A

VEGF family (vascular endothelial growth factor)
FGF family
TGF beta
PDGF

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4
Q

Give examples of extracellular matrix factors that inhibit angiogenesis

A

Thrombospondin-1
Angiostatin
Endostatin

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5
Q

Which surface receptors are involved in the regulation of angiogenesis

A

avb3

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6
Q

What are the 3 main ways of making blood vessels

A
  1. Vasculogenesis - mobilisation of endothelial progenitor cells (from the bone marrow)
  2. Angiogenesis - sprouting of new vessels (capillaries) from existing ones
  3. Arteriogenesis - collateral growth
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7
Q

Describe the process of sprouting angiogenesis

A
  1. 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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8
Q

Which factor activates angiogenesis in response to hypoxia

A

HIF: hypoxia-inducible transcription factor
Controls regulation of gene expression by oxygen
When there is plenty of oxygen, HIF is rapidly degraded. Hypoxia - proteolytic mechanisms to slow, allowing HIF to act in the nucleus. HIF increases transcription of VEGF and some other cytokines.

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9
Q

What factor regulates angiogenesis in response to hypoxia

A

pVHL: Von Hippel–Lindau tumor suppressor gene

Controls levels of HIF (binds to HIF-alpha -> destruction)

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10
Q

What are the 5 members of the VEGF family

A 
VEGF-A
VEGF-B
VEGF-C
VEGF-D
placental growth factor (PlGF)
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11
Q

What are the 3 tyrosine kinase receptors of VEGF

A

VEGFR-1
VEGFR-2
VEGFR-3
and co-receptors neuropilin (Nrp1 and Nrp2)

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12
Q

Which tyrosine kinase is the major mediator of VEGF-dependent angiogenesis

A

VEGFR-2

activates signalling pathways that regulate endothelial cell migration, survival, proliferation.

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13
Q

How is the tip cell selected and what does it do

A

The cell which receives the highest concentration of VEGF tells the adjacent cells that it alone will become the tip cell (via the Notch pathway)

Specialised tip cells lead the outgrowth of blood vessel sprouts up the VEGF gradient (towards hypoxia)

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14
Q

What are notch receptors and ligands

A

Membrane-bound proteins that associate through their extracellular domains
The intracellular domain of Notch (NICD) translocates to the nucleus and binds to the transcription factor RBP-J

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15
Q

Explain the process of tip cell selection

A
  1. In stable blood vessels, Dll4 and Notch signalling maintain quiescence
  2. VEGF activation increases expression of Dll4
  3. Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
  4. Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
  5. Adjacent cells (Stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation.
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16
Q

What is the role of macrophages in angiogenesis

A

Participate in vessel anastomosis
Macrophages carve out tunnels in the extra cellular matrix (ECM), providing avenues for capillary infiltration
Tissue-resident macrophages can be associated with angiogenic tip cells during anastomosis

17
Q

What is the role of platelets in angiogenesis

A

Link between cancer progression and thrombocytosis
Activated platelets are a source of VEGFA, PDGFs and FGF2
Tumours cause platelet activation, aggregation and degranulation

18
Q

Explain the angiopoietin-Tie2 ligand-receptor system

A

Ang-1 and Ang-2 are antagonistic ligands of the Tie2 receptor

Ang-1 binding to Tie2 promotes vessel stability and inhibits inflammatory gene expression

Ang-2 antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis

19
Q

How do tumours smaller than 1mm3 receive oxygen

A

Receives enough oxygen and nutrients by diffusion from existing vasculature

20
Q

How do tumours bigger than 1mm3 receive oxygen

A

Require new blood vessels to continue growing
Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels.
Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

21
Q

What is the angiogenic switch

A

A discrete step in tumour development that can occur at different stages in the tumour-progression pathway, depending on the nature of the tumour and its microenvironment

22
Q

Describe how tumour blood vessels are architecturally different to normal vessels

A

Irregularly shaped, dilated, and twisted
Not organised into definitive arterioles, capillaries, and venules
Leaky and haemorrhagic, with Perivascular cells more loosely associated

23
Q

What are the potential approaches to compromising tumour vasculature

A
  • inhibiting ECM breakdown, signal transduction or endothelial cell function (e.g. proliferation, migration, tube formation)
  • blocking activators of angiogenesis
  • antagonising receptors
  • damaging the existing tumour vasculature
24
Q

Give an example of an endogenous inhibitor of angiogenesis

A

Endostatin

Giving additional endostatin to cancer patients can significantly reduce the rate of growth of cancer

25
Q

Give an example of a drug used in cancer treatment that involves inhibition of angiogenesis

A

Bevacizumab is a humanised anti-VEGF mAb
Avastin is its trade name.
Used as part of a combination of therapies

26
Q

Explain the need for balance in inhibiting angiogenesis with drugs

A

Just eliminating pro-angiogenic molecules causes inadequate vasculature, and chemotherapy drugs cannot reach the tumour to kill it
Enough anti-angiogenic compounds are given to balance the surplus of pro- angiogenic ones

27
Q

What are the side effects of bevacisumab/avastin

A
  • GI perforation
  • hypertension
  • proteinuria
  • venous thrombosis
  • haemorrhage
  • wound healing complications
28
Q

Other than cancer treatment, what else can Bevacizumab/avastin be used for

A

Successful in stopping retinal vascularisation in macular degeneration
Coronary artery disease (use of a catheter to penetrate the blockage)

Y2 Cancer (16 decks)

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