Angiogenesis

Question 1

What is angiogenesis

Answer 1

The formation of new capillaries from pre-existing blood vessels

Question 2

What are the 2 types of abnormal angiogenesis

Answer 2

1. insufficient vessel growth
2. excessive vessel growth

Question 3

Describe the process of tumour angiogenesis

Answer 3

1. tumour starts due to the rise in oncogenes and loss of tumour suppressor gene function. At this point they are limited in growth due to the lack of oxygen and delivery of nutrients
2. Tumour cell becomes hypoxic this causes the angiogenic switch where hypoxia inducible factors stabilise and increase gene expression that initiate new blood vessel growth - angiogenic factors get released from the tumour and act on the nearest capillaries
3. angiogenesis forms and provides oxygen and nutrients to the tumour which causes growth and allows for metastasis

Question 4

What are angiogenic factors

Answer 4

factors produced by the tumour cells that stimulate directional growth of the endothelial cells

Question 5

Name 3 angiogenic factors

Answer 5

VEGF
FGF 2
Ang 2

Question 6

Describe the mechanism of action of Avastin (Bevacizumab)

Answer 6

it is a monoclonal antibody that inhibits VEGF receptors on endothelial cells to prevent VEGF secreted by the tumour cells from binding which prevents downstream signalling and angiogenesis

Question 7

Where are angiogenic factors stored/secreted

Answer 7

secreted from the tumour cells

or

stored and bound to components of the extracellular matrix and released by enzymes called matrix metalloproteinases (encoded by the gene MMP-2)

Question 8

Describe the mechanism of action of Sunitinib (Sutent)

Answer 8

receptor tyrosine kinase with anti-VEGF (R1,R2,R3) activity

small molecule

it competes with the ATP binding site and prevents receptor dimerisation this prevents autophosphorylation and activation of the receptor tyrosine kinases preventing downstream signalling

Question 9

What is an on-target side effect of angiogenic drugs, how does this happen

Answer 9

Hypertension

Normally VEGF will bind to receptor and this causes vasodilation by the release of nitric oxide on smooth muscle cells

inhibition of VEGF binding and signalling can cause vasoconstriction by upregulating the release of endothelin-1 and capillary reduction, this increases vascular resistance which causes hypertension

Question 10

What is VEGF important for

Answer 10

endothelial cell homeostasis

Question 11

What are 2 main limitations of angiogenic drugs

Answer 11

1. they aren’t a cure
2. acquired resistance - tumour will eventually upregulate another pathway of angiogenesis. The vessel regression will cause regions of hypoxia, angiogenic switch - hypoxia inducible factors stabilise, which increase gene expression and initiate new vessel growth - angiogenic factors are secreted out of tumour and act on the nearest capillary

Question 12

What does HIF-2a do

Answer 12

drives VEGF production and release

Question 13

Name a HIF-2a inhibitor

Answer 13

Belzutifan