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MCD > Cancer 7: angiogenesis > Flashcards

Cancer 7: angiogenesis Flashcards

1
Q

What is angiogenesis?

A

the formation of a new blood vessel from pre-existing blood vessels

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2
Q

What are the three ways of making blood vessels?

A
  • vasculogenesis
  • angiogenesis
  • arteriogenesis
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3
Q

What are the basic steps of sprouting?

A
  • growth factors are released that activate the endothelium cells to undergo a conformational change and send out filopodia in the direction of these factors
  • the end of the tip cell is modified to do this and they keep on moving until they interact with another tip cell, they fuse and stabilise
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4
Q

What is the main trigger for angiogenesis?

A

hypoxia

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5
Q

How does angiogenesis by hypoxia work?

A

there is a transcription factor called HIF that is normally inhibited by Von Hippel Lindau
-in hypoxia Von Hippel Lindel does not bind to HIF, so it can translocate to the nucleus and drive the expression of genes involved with angiogenesis

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6
Q

What are vascular endothelial growth factors?

A

-a family of 5 members: VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor

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7
Q

What are the three tyrosine kinase receptors?

A

VEGFR-1,2 and 3 and co receptors neuropilin

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8
Q

Which receptor is key in angiogenesis?

A

VEGFR-2

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9
Q

What is the role of tip cells in sprouting angiogenesis?

A

they lead the growth of blood vessel cells towards gradients of VEGF
- a pathway called notch is crucial for the selection for tip cell

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10
Q

What is the canonical notch signalling pathway?

A
  • the notch ligand binds to the notch receptor, activating it by cleaving the intracellular domain (NICD)
  • this then translocates to the nucleus and binds to transcription factor RBP-J
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11
Q

Chemically how are notch cells selected for?

A
  • in stable blood vessels, DII4 and notch signalling remain minimal
  • VEGF activation increases the expression of DII4
  • DII4 drives notch signalling which inhibits the expression of VEGFR2 in the adjacent cell
  • the cells either side recognise their role as stalk cells and divide to push the tip cell forward
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12
Q

What happens once the tip cell and sprout cells have been identified?

A
  • the cell needs to progress forward through the ECM
  • macrophages also have an important role as they have been shown to carve out tunnels in the ECM, guiding growth
  • proliferating stalk cells attract pericytes and deposit basement membranes to become stabilized
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13
Q

What needs to happen after tip cells have fused?

A
  • the stalk cells separate to form a patent tube and now needs to STABILISE
  • this involves reforming the endothelial monolayer barrier and recruiting pericytes
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14
Q

What is the role of cadherin in endothelial cells?

A
  • lines the junctions of endothelial cells
  • important in contact inhibition of cell growth
  • promote survival of endothelial cells
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15
Q

what is the role of VE-cadherin?

A

essential for vessel stabilisation and quiescence

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16
Q

what are the roles of pericytes?

A

important in the stabilisation of new blood vessels e.g. produce proteins like Angiopoietin 1

17
Q

What are mural cells?

A

smooth muscle cells AND pericytes

18
Q

What is the angiopoietin-Tie2 ligand receptor system?

A

-when ang-1 binds to Tie2 this promotes vessels stability and inhibits inflammatory gene expression
PROMOTES QUIESCENCE
-Ang2 promotes vascular instability and VEGF dependant angiogenesis

19
Q

How do tumours get their blood supply?

A
  • tumours less than 1 mm3 receive oxygen and nutrients by diffusion
  • larger tumours require a new vessel network- this stimulates migration, proliferation and neovessel formation by endothelial cells in adjacent established vessels
20
Q

What is the angiogenic switch?

A

the point at which a tumour reaches a certain size where diffusion is no longer sufficient, some of the cells become hypoxic and send angiogenic signals

21
Q

What are the characteristics of tumour blood vessels? (5)

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
  • some tumours may recruit endothelial progenitor cells from the bone marrow
22
Q

Which cells promote tumour angiogenesis?

A
  • fibroblasts
  • pericytes
  • platelets
23
Q

How do platelets lead to tumour angiogenesis?

A

activated platelets are a source of:

  • proangiogenic factors: VEGFA, PDGFs, FGF2
  • angiostatic molecules: thrombospondin 1, PAL1 and endostatin
24
Q

What are the side effects of avastin?

A
  • GI perforation
  • Hypertension
  • Proteinuria
  • Venous thrombosis
  • Haemorrage
  • Wound healing complications
25
Q

Why does avastin have limited efficiency?

A
  • VEGF inhibition aggravates hypoxia and so increasing the tumours release of other angiogenic factors
  • tumour vessels may be less sensitive to VEGF inhibition due to vessel lining
  • tumour cells that recruit pericytes maybe less responsive to VEGF therapy
26
Q

What is the anti-angiogenic therapy strategy?

A

to normalise vasculature

  • reduce hypoxia
  • increase efficacy of conventional therapies
27
Q

What is lucentis?

A

a modified version of Avastin used to treat age macular degeneration

MCD (13 decks)

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