Angiogenesis Flashcards
What is HIF?
Hypoxia inducible factor
What happens to HIF-1alpha in normal conditions?
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
What happens to HIF-1alpha in low oxygen (hypoxic) conditions?
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
Does pH increase or decrease in hypoxic conditions?
Decrease (more acidic)
What is an in situ tumour?
Small tumours still in place of origin
Describe the angiogenic switch
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
Describe the structure of nascent vessels
Tube of endothelial cells
Describe the structure of capillaries
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)
Describe the structure of arteries + veins
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
What is the drainage system?
Lymphatic system
What is vasculogenesis?
Formation of blood vessels itself
What is angiogenesis?
Formation of new vasculature (new blood vessels) Via sprouting intussusception (to form micro vessels) bridging (micro vessels in 1 big vessel)
What is the precursor for most blood vessels?
Angioblasts/haemangioblasts (stem cell)
What regulates angiogenesis?
Balance of endogenous pro-angiogenic factors + anti-angiogenic factors
Name 3 pro-angiogenic factors
VEGF (vascular endothelial growth factor)
bFGF (basic fibroblast growth factor)
PDGF (platelet-derived growth factor)
Name 3 anti-angiogenic factors
Endostatin
Angiostatin
Thrombospondin
Too much of which type of factor is seen in tumours?
Too much pro-angiogenic factors
What happens to the vasculature in tumours?
Irregular
Differences in width
Spaces formed
What happens to tumour cells as they get further away from blood vessels?
Enter quiescent phase (G0)
Describe the mechanism of angiogenesis
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
Are endothelial cells slow of fast at dividing?
Slow
How is abnormal tumour vasculature different to normal vasculature?
Leaky pores increase fluid pressure
- > tumour cells can leak in or out
- > blocks drugs + oxygen transport
- > painful tumour swelling
Acidic environment
-> resistance to drugs
What does a drug ending in “ab” mean?
Monoclonal antibodies
-> targets ligand or receptor
What does a drug ending in “ib” mean?
Small molecule inhibitors
-> inhibit activity by competing for binding site
What are the 5 categories of anti-angiogenics?
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
Name 3 drugs that targets VEGF pathway
Avastin = Neutralises VEGF ligand Sutent = Block receptor Iressa = Block VEGF production
