Angiogenesis

Question 1

What is angiogenesis

Answer 1

formation of new capillaries from preexisting vessels

Migration and proliferation of EC

Question 2

What is vasculogenesis

Answer 2

formation of new vessels from circulating bone marrow derived EPC
works in embryo/tumour development

Question 3

What is arteriogenesis

Answer 3

Increase in calibre of preexisting arteriolar connections by recruitment of perivascular cells and ECM remodelling

Question 4

What are the steps of making a new capillary?

Answer 4

1. Pretease is released from activated EC
2. protease breaks down the base membrane
3. Migration of EC into interstitial space
4. EC proliferation
5. Formation of lumen for new capillary
6. Formation of new basement membrane with the recruitment of pericytes (surround capillaries)
7. Fuse with new vessels
8. Blood flow initiates

Question 5

Tumour growth -hypoxia

Answer 5

If it is far away, less access to oxygen (detect hypoxia –> pro-angiogenesis)

Question 6

Metastasis is angiogenesis dependent

Answer 6

1. tumour cells must access vasculature of primary tumour

2. It must induce angiogenesis once they start growing in the target organ

Question 7

What is VEGF

and what determines its gene expression?

Answer 7

Regulate normal embryonic vasculogenesis and angiogenesis and tumour angiogenesis
gene expression effected by hypoxia

Question 8

Actions of VEGF

Answer 8

vasodilation
protein filtration
coagulation
EC proliferation and migration
EC survival
dendritic cell function hibition
hematopoiesis/ myelodpoiesis
Thyroid cell stimulation

Question 9

VEGF presence location

Answer 9

High concentration near the tumour,

low near the vessel

Question 10

Angiogenesis inhibitors target which cell?

Answer 10

Genetically stable microvascular endothelial cells (unstable ones can escape therapy)

Question 11

What does angiostatin do?

and where is it from?

Answer 11

Inhibit EC proliferation, circulating precursor EC proliferation and angiogenesis
It is from cleaved plasminogen enzymes produced from the tumour cells

Question 12

What does endostatin do?

and where is it from?

Answer 12

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

Question 13

What did Endostar do to to increase the protein purification, solubility and stability?

Answer 13

Add 9 AA to endostatin

Question 14

Bevacizumab MOA

Answer 14

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

Question 15

Ranibizumab MOA

Answer 15

VEGF inhibition prevents macular oedema and choroidal neovascularisation
prevent angiogenesis in proliferative neovascular eye disease
250x more expensive than bevacizumab

Question 16

Pegaptanib MOA

Answer 16

Anti VEGF 165 aptamer (that offers molecular recognition without immunogenicity)
For AMD

Question 17

Aflibercept MOA

Answer 17

Recombinant VEGFR fusion protein that binds to and inhibit VEGF A,B, and PIGF
For cancer and AMD

Question 18

Ramucirumab

Answer 18

FULLY human monoclonal antibody against VEGFR2

For cancer

Question 19

Are they pure VEGFR inhibitors?

Answer 19

NO none of them are pure

Question 20

What happens when anti-VEGF therapy is stopped?

Answer 20

rapid vascular regrowth of tumour

stability of vascular basement membrane

Question 21

What is vessel normalisation?

How do you do this?

Answer 21

Repair vascular abnormalities

By lowering VEGF signalling

Question 22

What are the drugs for vessel normalisation?

Answer 22

Thalidomide, Lenalidomide,pomalidomide

Question 23

Thalidomide MOA and use

Answer 23

Prevent bFGF and VEGF elicited angiogenesis
S-enantiomer = Teratogenic
R-enantiomer = For women’s morning sickness

Question 24

Lenalidomide use

Answer 24

Anti-angiogenic
Teratogenic
For multiple myeloma

Question 25

Pomalidomide use

Answer 25

MOST POTENT of the immunomodulatory drugs (IMiDs)
anti-angioenic
for multiple myeloma

Question 26

How to optimise anti-angiogenic effects?

Answer 26

by metronomic administration: small doses frequently

It can treat tumours resistant to the same chemotherapeutic agents

Question 27

Benefit of metronomic admin?

Answer 27

sustained suppression of circulating EPC

increased endogenous angiogenesis inhibitors

Question 28

what is lymphangiogenesis

Answer 28

Formation of lymphatic vessels from pre-existing lymphatic vessels

Question 29

What do lymphatic vessels do?

Answer 29

regulate tissue fluid homeostasis, immune cell trafficking, absorption of dietary fats

Question 30

When does lymphangiogenesis occur?

Answer 30

In adults during inflammation, injuries and tumour metastsis

Question 31

How can you detect first tumour dissemination (spread)?

Answer 31

Regional lymph node metastasis

Question 32

What VEGRs are activated which VEGF?

Answer 32

VEGF C & D activate VEGR3 –> lymphangiogenesis

Inhibiting VEGFR3 pathway suppresses lymph node metastasis