Angiogenesis Flashcards
What is angiogenesis
formation of new capillaries from preexisting vessels
Migration and proliferation of EC
What is vasculogenesis
formation of new vessels from circulating bone marrow derived EPC
works in embryo/tumour development
What is arteriogenesis
Increase in calibre of preexisting arteriolar connections by recruitment of perivascular cells and ECM remodelling
What are the steps of making a new capillary?
- Pretease is released from activated EC
- protease breaks down the base membrane
- Migration of EC into interstitial space
- EC proliferation
- Formation of lumen for new capillary
- Formation of new basement membrane with the recruitment of pericytes (surround capillaries)
- Fuse with new vessels
- Blood flow initiates
Tumour growth -hypoxia
If it is far away, less access to oxygen (detect hypoxia –> pro-angiogenesis)
Metastasis is angiogenesis dependent
- tumour cells must access vasculature of primary tumour
2. It must induce angiogenesis once they start growing in the target organ
What is VEGF
and what determines its gene expression?
Regulate normal embryonic vasculogenesis and angiogenesis and tumour angiogenesis
gene expression effected by hypoxia
Actions of VEGF
vasodilation protein filtration coagulation EC proliferation and migration EC survival dendritic cell function hibition hematopoiesis/ myelodpoiesis Thyroid cell stimulation
VEGF presence location
High concentration near the tumour,
low near the vessel
Angiogenesis inhibitors target which cell?
Genetically stable microvascular endothelial cells (unstable ones can escape therapy)
What does angiostatin do?
and where is it from?
Inhibit EC proliferation, circulating precursor EC proliferation and angiogenesis
It is from cleaved plasminogen enzymes produced from the tumour cells
What does endostatin do?
and where is it from?
it binds to a5b1 on EC (important for migration), interfere with eNOs, inhibit VEGF receptor, MMP2 (degradation of membrane), EC motility and, cyclin D1 in EC
It is from collagen IV, stored in the platelets
What did Endostar do to to increase the protein purification, solubility and stability?
Add 9 AA to endostatin
Bevacizumab MOA
Humanised anti VEGF antibody
bind to and neutralise all human VEGF A
inhibit binding of VEGF to its receptor on EC
Can be used offlabel
Ranibizumab MOA
VEGF inhibition prevents macular oedema and choroidal neovascularisation
prevent angiogenesis in proliferative neovascular eye disease
250x more expensive than bevacizumab
Pegaptanib MOA
Anti VEGF 165 aptamer (that offers molecular recognition without immunogenicity)
For AMD
Aflibercept MOA
Recombinant VEGFR fusion protein that binds to and inhibit VEGF A,B, and PIGF
For cancer and AMD
Ramucirumab
FULLY human monoclonal antibody against VEGFR2
For cancer
Are they pure VEGFR inhibitors?
NO none of them are pure
What happens when anti-VEGF therapy is stopped?
rapid vascular regrowth of tumour
stability of vascular basement membrane
What is vessel normalisation?
How do you do this?
Repair vascular abnormalities
By lowering VEGF signalling
What are the drugs for vessel normalisation?
Thalidomide, Lenalidomide,pomalidomide
Thalidomide MOA and use
Prevent bFGF and VEGF elicited angiogenesis
S-enantiomer = Teratogenic
R-enantiomer = For women’s morning sickness
Lenalidomide use
Anti-angiogenic
Teratogenic
For multiple myeloma
Pomalidomide use
MOST POTENT of the immunomodulatory drugs (IMiDs)
anti-angioenic
for multiple myeloma
How to optimise anti-angiogenic effects?
by metronomic administration: small doses frequently
It can treat tumours resistant to the same chemotherapeutic agents
Benefit of metronomic admin?
sustained suppression of circulating EPC
increased endogenous angiogenesis inhibitors
what is lymphangiogenesis
Formation of lymphatic vessels from pre-existing lymphatic vessels
What do lymphatic vessels do?
regulate tissue fluid homeostasis, immune cell trafficking, absorption of dietary fats
When does lymphangiogenesis occur?
In adults during inflammation, injuries and tumour metastsis
How can you detect first tumour dissemination (spread)?
Regional lymph node metastasis
What VEGRs are activated which VEGF?
VEGF C & D activate VEGR3 –> lymphangiogenesis
Inhibiting VEGFR3 pathway suppresses lymph node metastasis
