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Year 2 - Cancer > Cancer 7 > Flashcards

Cancer 7 Flashcards

1
Q

what is the definition of angiogenesis?

A
  • Angiogenesis is the formation of a new blood vessel from pre=existing blood

vessels

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2
Q

what are the 3 ways to make blood vessels?

A
  • Vasculogenesis

in the embryo, the contribution of bone marrow progenitor cells is very important in the early stages of blood vessel formation

  • Angiogenesis

the most common way in which new blood vessels are formed eg. in wound healing or in the menstrual cycle

  • Arteriogenesis

collateral growth that is dependent on shear stress and external factors like macrophages

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3
Q

what are the regulators of angiogenesis?

A
  • there is a large number of regulators of angiogenesis required
  • we need both inhibitors and activators
  • some are crucial eg. VEGF
  • some or only required for modulation eg. VWF
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4
Q

what are the stages of sprouting angiogenesis?

A
  • tip/ stalk cell selection
  • tip cell drives the sprouting
  • the stalk cells proliferate
  • branching coordination
  • stalk elongation
  • tip cell fusion
  • lumen formation
  • perfusion and vessel maturation
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5
Q

what is the most important signal to form new blood vessels?

A
  • hypoxia
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6
Q

how does hypoxia trigger angiogenesis?

A

in the presence of oxygen =

  • HIF is inhibited by binding to Von Hippel - Lindau factor

in the case of hypoxia =

  • the proteins detach
  • the von Hippel - Lindau is removed from HIF
  • HIF goes into the nucleus
  • binds to DNA
  • drives the expression of genes that promote angiogenesis eg. VGEF
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7
Q

what is VGEF?

vascular endothelial growth factors

A
  • family of 5 members
  • VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PIGF)
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8
Q

what are the VGEF receptors?

A
  • three tyrosine receptors
  • VEGFR 1, VEGFR 2, VEGFR 3 and co-receptors neuropilin
  • VEGFR 2 is a major mediator of the VEGF dependent angiogenesis activating signaling pathways that regulate endothelial cell migration, survival , and proliferation
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9
Q

what are the co-receptors for VEGF?

A
  • neuropilin - 1
  • neuropilin - 2
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10
Q

what is the role of VEGF in angiogenesis?

A
  • VEGF is produced by something in the environment
  • VEGF binds to VEGF receptor in the environment
  • the cell that VEGF binds to becomes the tip cell
  • the tip cells tell the surrounding cells to become stalk cells
  • tip cells lead the outgrowth of blood- vessel sprouts towards gradients of VEGF
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11
Q

what is the canonical notch pathway?

A
  • the Notch ligand ( Delta-like ligand 4 (Dll4)) and Notch receptor bind
  • this binding causes the cleavage of the notch intracellular domain (NICD)
  • NICD goes into the nucleus and acts as a transcriptional regulator RBP- J and regulates transcription
  • When a tip cell is chosen, it begins to express notch ligand which binds to the stalk cells’ notch receptors, to identify the tip cell
  • The stalk cells then begin to divide and push the tip cell towards the growth factor
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12
Q

how does VEGF affect the Canonical Notch Signalling Pathway?

A
  • VEGF will activate endothelial cells in a capillary and increase expression of Dll4
  • Dll4 then drives the Notch signaling and inhibits the expression of VEGFR2 in the adjacent cell
  • By doing this, the cells on either side of the tip cell will then recognize their role as stalk cells that have to divide and push the tip cell forward
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13
Q

how does sprout outgrowth take place?

A
  • once the tip cells and stalk cells have been identified the sprout needs to progress further
  • The cells will interact with the ECM and there will be guidance systems in place
  • Macrophages also have an important role in vessel anastomosis
  • macrophages carve out tunnels in the ECM thereby providing avenues for subsequent capillary infiltration
  • Tissue-resident macrophages were shown to be associated with angiogenic tip cells during anastomosis
  • macrophages appear to help stabilize newly formed vessels by promoting tip cell fusion
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14
Q

what is the role of platelets in angiogenesis?

A
  • platelets are modulators of angiogenesis
  • they contain both initiators and inhibitors for angiogenesis
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15
Q

what is the stabilization and quiescence stage of angiogenesis?

A
  • once the tip cells have fused and the stalk cells are separating to form a patent tube, the new vessel needs to stabilize
  • stabilization involves reforming the endothelial monolayer barrier and recruiting neural cells
  • as well as switching off the active angiogenesis process
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16
Q

how are the junctions between the cells formed?

A
  • There are proteins (cadherins) on the membranes of both cells that bind in a homophilic way
17
Q

why are the cadherin interactions at the junctions so important?

A
  • Cadherin is an important protein that lines the junctions of endothelial cells
  • VE-Cadherin is essential for vessel stabilization and quiescence
  • the homophilic interaction between the cadherins on the endothelial cells mediates the adhesion between endothelial cells and is important for signaling
  • The cadherin interactions are also important in contact inhibition of cell growth
  • cadherins also promote the survival of the endothelial cells
18
Q

why are pericytes recruited at the junctions?

A
  • they produce a load of proteins that are involved in stabilizing the vessel
  • specifically they produce Angiopoietin 1 that goes on to control junctional systems eg. the notch system
  • The angiopoietin/Tie- 2 system is specific to the endothelium
19
Q

what is the role of angiopoietin-Tie2 system?

explain the function of Angiopoietin 1?

explain the function of Angiopoietin 2?

A
  • The angiopoietin- Tie2 system is required to modulate the activity of the endothelial cells and revert them to quiescence (dormancy)
  • Tie 2 is a receptor that binds to Angiopoietin 1
  • when angiopoietin 1 binds to Tie 2 promotes quiescence
  • angiopoietin 2 is released when you need to form new blood vessels, respond to inflammation or destabilize the vasculature
  • Angiopoietin 2 antagonizes Ang-1 signaling and causes angiogenesis
20
Q

when do tumours require angiogenesis?

A
  • Tumours <1 mm^3 receive oxygen and nutrients by diffusion from host vasculature
  • when tumors grow larger than this they require new vessel networks
  • Tumors secrete angiogenic factors that stimulate the formation of new blood vessels
  • a newly vascularized tumor no longer depends on the host vasculature this , therefore facilitates its progressive growth
21
Q

what is the angiogenic switch?

A
  • there is a point at which the tumour gets to a certain size where diffusion is no longer sufficient, so some cells of the tumour become hypoxic and send for angiogenic signals
22
Q
A
23
Q

why are the tumour blood vessels not properly formed?

A
  • these are not properly formed because the angiogenesis signals are hypoxic
  • the signals are imbalenced
24
Q

what are the features of tumour blood vessels?

A
  • Irregularly shaped, dilated, tortuous
  • not organized into venules arteries and capillaries
  • Leaky and haemorrhagic
  • Perivascular cells often become
    loosely associated

*

25
Q

what is the role of platelets in tumor angiogenesis

A
  • there is a link between cancer progression and thromboctyosis
  • activated platelets are a source of pro-angiogenic factors
  • tumors cause platelet activation which might potentially be promoting angiogenesis
26
Q

how does anti - VGEF antibodies treatment work?

(Avastin)

A
  • This is also called Bevacizumab
  • this works by preventing angiogenesis by blocking VGEF
  • however Avastin has limited efficacy and lots of side effects

o Proteinuria

o Venous thrombosis

o Haemorrhage

o Wound healing complications

o perforation Hypertension

the drug has lots of side effects because VEGF is essential for the homeostasis of the endothelium

there was no overall survival advantage to chemotherapy

27
Q

what are the two main methods of the tumor being resistant to VEGF blockade?

A
  • The tumour adopts an evasive strategy and adapts to bypass the specific angiogenic blockade
  • Intrinsic or pre-existing difference = the idea that a particular tumour in particular place in a particular person, was not very sensitive to VEGF anyway, so knocking out VEGF made little difference
28
Q

who did anti-angiogenetic medication aid?

A
  • aided those with Age-related macular degeneration (AMD)
29
Q

who might pro-angiogenic therapy help?

A
  • may help people following an occlusion of an artery
  • There have been attempts to inject VEGF into the cardiac tissue soon after occlusion with the hope of stimulating neovascularisation that will reduce the damage due to ischaemia
30
Q

how does anti VEGF therapy help those with Age-related macular degeneration?

A
  • Though Avastin wasn’t designed for AMD, some clinicians tried it out and found that it was effective in AMD
31
Q

what is tumour on a chip?

A
  • tumours are complex 3D structures
  • tumour on a chip aims to replicate this environment
  • it would be much more reliable than animal testing/drug screens
  • we can grow our own blood vessels on the chip

Year 2 - Cancer (15 decks)

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