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DNA and Disease > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

What is HIF?

A

Hypoxia inducible factor

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2
Q

What happens to HIF-1alpha in normal conditions?

A

1) Oxygen causes OH groups to be added to HIF (by prolyl hydroxylase)
2) VHL protein recognises this + binds to it forming a complex
3) This leads to its degradation

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3
Q

What happens to HIF-1alpha in low oxygen (hypoxic) conditions?

A

1) HIF goes to the nucleus
2) HIF is associated w/ ARNT + binds to specific DNA sequences (HREs = hypoxia-response elements)

HIF is NOT degraded

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4
Q

Does pH increase or decrease in hypoxic conditions?

A

Decrease (more acidic)

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5
Q

What is an in situ tumour?

A

Small tumours still in place of origin

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6
Q

Describe the angiogenic switch

A

1) When tumour cells are in hypoxic conditions, they secrete angiogenic proteins which diffuse to capillaries
2) Results in division + growth of vasculature
3) Tumour can now have access to oxygen + nutrients -> proliferation

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7
Q

Describe the structure of nascent vessels

A

Tube of endothelial cells

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8
Q

Describe the structure of capillaries

A

Tube of endothelial cells
= continuous (in muscle)
= fenestrated/holey (in kidney/endocrine glands)
= discontinuous (in liver sinusoids)

Surrounded by basement membrane embedded w/ sparse layer of pericytes (involved in angiogenesis)

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9
Q

Describe the structure of arteries + veins

A

Tube of endothelial cells

Surrounded by basement membrane embedded w/ layer of pericytes

Smooth muscle cell layer
= More regularly arranged in arteries than in veins

Lumen smaller in arteries than in veins

Fibroblasts

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10
Q

What is the drainage system?

A

Lymphatic system

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11
Q

What is vasculogenesis?

A

Formation of blood vessels itself

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12
Q

What is angiogenesis?

A 
Formation of new vasculature
(new blood vessels)
Via
sprouting
intussusception (to form micro vessels)
bridging (micro vessels in 1 big vessel)
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13
Q

What is the precursor for most blood vessels?

A

Angioblasts/haemangioblasts (stem cell)

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14
Q

What regulates angiogenesis?

A

Balance of endogenous pro-angiogenic factors + anti-angiogenic factors

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15
Q

Name 3 pro-angiogenic factors

A

VEGF (vascular endothelial growth factor)
bFGF (basic fibroblast growth factor)
PDGF (platelet-derived growth factor)

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16
Q

Name 3 anti-angiogenic factors

A

Endostatin
Angiostatin
Thrombospondin

17
Q

Too much of which type of factor is seen in tumours?

A

Too much pro-angiogenic factors

18
Q

What happens to the vasculature in tumours?

A

Irregular
Differences in width
Spaces formed

19
Q

What happens to tumour cells as they get further away from blood vessels?

A

Enter quiescent phase (G0)

20
Q

Describe the mechanism of angiogenesis

A

1) Hypoxia triggers release of pro-angiogenic factors from tumour cells -> receptors on endothelial cells of pre-existing blood vessels
2) Secretion + activation of various proteolytic enzymes (e.g. matrix metalloproteinases (MMPs))
3) Proteolytic enzymes degrade the basement membrane + ECM + cause detachment of pericytes
4) Endothelial cells (activated by growth factors) to form tip cells which migrate towards tumour (along angiogenic factor gradient)
5) Tip cell also divide forming primitive blood vessel
6) Tip cells mature -> endothelial cells to form a tube
7) Other molecules increase width of blood vessels
8) Pericytes attach -> stabilise vessels
9) Other tip cells make network
10) PDGF (secreted from tumour + blood vessel) activates receptors for integrin -> allow cells to move along gradient

21
Q

Are endothelial cells slow of fast at dividing?

A

Slow

22
Q

How is abnormal tumour vasculature different to normal vasculature?

A

Leaky pores increase fluid pressure

  • > tumour cells can leak in or out
  • > blocks drugs + oxygen transport
  • > painful tumour swelling

Acidic environment
-> resistance to drugs

23
Q

What does a drug ending in “ab” mean?

A

Monoclonal antibodies

-> targets ligand or receptor

24
Q

What does a drug ending in “ib” mean?

A

Small molecule inhibitors

-> inhibit activity by competing for binding site

25
Q

What are the 5 categories of anti-angiogenics?

A

Inhibitors of angiogenic growth factors (VEGF, bFGF, PDGF)

MMP inhibitors

Analogs of endogenous inhibitors of angiogenesis

Inhibitors of cellular adhesion molecules (integrins)

Molecules w/ undefined mechanisms

26
Q

Name 3 drugs that targets VEGF pathway

A 
Avastin = Neutralises VEGF ligand
Sutent = Block receptor
Iressa = Block VEGF production

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