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Cancer > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

Angiogenesis

A

New blood vessel formation

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2
Q

Sprouting angiogenesis

A
  • tip/stalk cell selection
  • tip cell navigation and stalk cell proliferation
  • branching coordination
  • stalk elongation, tip cell fusion and lumen formation
  • perfusion and vessel maturation
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3
Q

How to make a blood vessel

A

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4
Q

Regulators of angiogenesis: Activators

A 
GROWTH FACTORS
-VEGF family
-FGF family
-TGF-beta
-PDGF
SOLUBLE FACTORS
-IL-6
-Factor XIII
-TNF-alpha
CELL SURFACE RECEPTORS
-Alpha-V beta-3
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5
Q

Regulators of angiogenesis: Inhibitors

A 
EXTRACELLULAR MATRIX
-Thrombospondin-1
-Angiostatin
-Endostatin
SOLUBLE FACTORS
-sVEGF-R
-IL-10
-IL-12
-TNF-alpha
CELL SURFACE RECEPTORS
-Alpha-V beta-3
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6
Q

Regulators of angiogenesis: Maturation and Integrity

A
  • VE-Cadherin (Junctions)
  • Angiopoietin/Tie2
  • Notch pathway
  • ERG pathway
  • Platelets
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7
Q

Hypoxia

A

A lower-than-normal concentration of oxygen in arterial blood

  • HIF (hypoxia-inducible transcription factor=controls regulation of gene expression by oxygen)
  • pVHL (Von-Hippel-Lindau tumour suppressor gene=controls levels of HIF)
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8
Q

Vascular Endothelial Growth Factor (VEGF) and its receptors

A
  • Family of 5 members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF)
  • Three tyrosine kinase receptors: VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3; and co-receptors neuropilin (Nrp1 and Nrp2)
  • VEGFR-2 is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival, proliferation
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9
Q

Tip cells and sprouting angiogenesis

A

-specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of VEGF

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10
Q

Canonical Notch signalling pathway

A
  • Notch receptors and ligands=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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11
Q

Selection of tip cells: VEGF/Notch signalling

A
  • In stable blood vessels, Dll4 and Notch signalling maintain quiescence
  • VEGF activation increases expression of Dll4
  • Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
  • Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
  • Adjacent cells (Stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation
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12
Q

Sprout outgrowth and guidance

A

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13
Q

Macrophage participation in vessel anastomosis

A
  • Macrophages play a significant role in both physiological and pathological angiogenesis
  • 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
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14
Q

Platelet role in angiogenesis

A

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15
Q

Stabilisation and quiescence

A

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16
Q

Tight junctions and adherens junctions in endothelial cells

A
  • Constitutively expressed at junctions
  • Homophilic interaction mediates adhesion between endothelial cells and intracellular signalling
  • Controls contact inhibition of cell growth
  • Promotes survival of EC
17
Q

Mural cells (pericytes) in stabilising neovessels

A

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18
Q

Signalling pathways controlling stability: 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

Increase in Ang-2 plasma levels during:

A
  • Congestive heart failure
  • Sepsis
  • Chronic kidney disease
20
Q

Tumour angiogenesis and neovasculature

A

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21
Q

The angiogenic switch

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

Tumour blood vessels

A

-irregularly shaped, dilated, tortuous
not organized into definitive venules, arterioles and capillaries
-leaky and haemorrhagic, partly due to the overproduction of VEGF
-perivascular cells often become loosely associated
-some tumours may recruit endothelial progenitor cells from the bone marrow

23
Q

Tumour neovasculature: comparative tortuosity (twisted) and disorganisation

A

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24
Q

Multicellular response promotes tumour angiogenesis

A
  • Cancer-associated fibroblasts (CAFs) secrete extracellular matrix; pro-angiogenic growth factors, (VEGFA; FGF2; CXCL12; PDGFC)
  • Pericytes are loosely associated with with tumour-associated blood vessels (TABVs), and this favours chronic leakage in tumours. This is enhanced by angiopoietin 2 (ANGPT2)
  • Platelets release pro-angiogenic mediators and proteases that support the proliferation and activation of CAFs, such as PDGFB and TGFβ
25
Q

Role of platelets in tumour angiogenesis

A

LINK BETWEEN CANCER PROGRESSION AND THROMBOCYTOSIS

Activated platelets are a source of:

  • pro-angiogenic factors: VEGFA, platelet-derived growth factors (PDGFs), FGF2
  • angiostatic molecules: thrombospondin 1, plasminogen activator inhibitor 1 (PAI1), endostatin
  • Tumours cause platelet activation, aggregation and degranulation
  • Disrupting platelet function does not obviously impair tumour angiogenesis, however the overall outcome of platelet activation in tumours appears to be pro-angiogenic
26
Q

Therapeutic strategies to inhibit VEGF signalling

A

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27
Q

VEGF inhibition by soluble VEGFR1 (Flt-1) reduces tumour growth

A
  • Cells stably transfected with control or sFlt-1 plasmid to promote Flt-1 (VEGFR1) expression
  • VEGFR1 binds to VEGF and “mops it up” preventing it from stimulating angiogenesis
  • Flt-1 expression reduces tumor growth in vivo, without affecting tumor cell growth in vitro: effect on vasculature
28
Q

Anti-VEGF humanised MAb (Avastin)

A

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29
Q

Avastin side effects

A
  • GI perforation
  • Hypertension
  • Proteinuria
  • Venous thrombosis
  • Haemorrhage
  • Wound healing complications
30
Q

Limited efficacy of Avastin

A
  • No overall survival advantage over chemo alone
  • No quality-of-life or survival advantage
  • In some cases benefits are transitory, followed by a restoration of tumour growth and progression
  • In other cases there is no objective benefit
31
Q

Potential mechanisms of resistance to anti-VEGF therapy in cancer

A
  • VEGF inhibition aggravates hypoxia increasing tumour’s production of other angiogenic factors or increases tumour invasiveness
  • Tumours vessels maybe less sensitive to VEGF inhibition due to vessel lining by tumour cells or endothelial cells derived from tumours
  • Tumour cells that recruit pericytes maybe less responsive to VEGF therapy
32
Q

The future for anti-angiogenic therapy

A

-Anti-angiogenic therapy in combination with other anti-cancer therapies
-Resistance: combinatorial strategies involving angiogenesis inhibition & drugs targeting resistance mechanisms
-Novel non-VEGF targets – novel molecular mechanism
-Anti-angiogenic therapy in other diseases:
Retina vascularization (diabetic retinopathy, wet AMD)

33
Q

Finding novel molecular mechanism cell by cell: single cell RNASeq of tumour endothelium

A

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34
Q

Age-related macular degeneration (AMD)

A

Abnormal growth of choroidal blood vessels

  • ‘Leaky’ vessels cause oedema
  • Visual impairment
35
Q

Anti-VEGF therapy for age-related macular degeneration (AMD): Lucentis

A
  • AMD is the main cause of blindness
  • Avastin not FDA approved for AMD, but used off-label
  • Lucentis developed by Genentech from the parent molecule Avastin
  • June 2006: FDA approval for Lucentis for AMD
  • High efficacy of both treatments in maintaining or improving vision
  • Many patients become refractory to treatment >2 years
  • Ranibizumab (Lucentis)=$2,023 per dose (up to 12 injections per year)
  • Bevacizumab (Avastin)=$55 per dose.
36
Q

How to find better therapeutic strategies to inhibit angiogenesis in cancer

A
  • Tumours are complex three-dimensional (3D) structures with their own unique microenvironments
  • We lack good in-vitro models - our understanding of tumour behaviour in a complex 3D environment is limited and drug screens are often misleading
  • Studies are performed on cell lines growing as two-dimensional (2D) monolayers, which do not mimic the complex interplay between tumour cells and their extracellular environment
  • The phenotype of tumour cells when cultured in 2D vs 3D is different
  • Crucially, tumours receive nutrients and therapeutics through the vasculature, which is not included in any in-vitro tumour models
37
Q

‘tumour-on-a-chip’ platform

A

-develop a microphysiological system that incorporates human cells in a 3D extracellular matrix, supported by perfused human microvessels

Cancer (15 decks)

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