Cancer 8 - Angiogenesis

Question 1

What are the 3 ways to make a blood vessel?

Answer 1

1. Vasculogenesis - bone marrow progenitor cell
2. Angiogenesis - sprouting (most common - e.g. wound healing / menstrual cycle)
3. Arteriogenesis (collateral growth) - dependent on shear stress and external factors (e.g. macrophages)

Question 2

What is usually the trigger for angiogenesis?

Answer 2

Hypoxia

Question 3

What do tip cells move towards?

Answer 3

Growth factor

But tip cells do not actually divide - neighbouring cells divide and push the tip towards GF

Question 4

What are some essential pro-angiogenic mediators?

Answer 4

VEGF

Question 5

What is HIF and how is it regulated?

Answer 5

Hypoxia-inducible TF

It is a TF which is inhibited in normal conditions by Von-Hippel-Lindau (a TSG).
In hypoxic conditions, Von Hippel-Lindau not bound to HIF - HIF can translocate into nucleus and drive expression of genes involved in angiogenesis

HIF targets expression of VEGF

Question 6

What are the 5 families of VEGF

Answer 6

1. VEGF-A
2. VEGF-B
3. VEGF-C
4. VEGF-D
5. PIGF

Question 7

What are the 3 tyrosine kinase receptors for VEGF?

Answer 7

VEGFR-1
VEGFR-2
VEGFR-3

Question 8

What are the 2 coreceptors for VEGF

Answer 8

1. Neuropilin-1 (Nrp-1)

2. Neuropilin-2 (Nrp-2)

Question 9

Which VEGF receptor is the major mediator for VEGF-dependent angiogenesis?

Answer 9

VGFR2

Question 10

Explain the notch pathway that is used for signalling of tip cells

Answer 10

1. Tip cell expresses notch ligand - binds to stalk cells notch receptors
2. Binding to the notch receptor activates the receptor through cleavage of NICD intracellular domain
3. NICD translocates to nucleus and binds to TF RBP-J where it regulates transcription.
4. Stalk cells divide and push tip cell towards the GF

(5. VEGF activation causes increased expression of notch ligand (DLL4)
6. DLL4 drives notch signalling - inhibits VEGFR2 expression in adjacent cell
7. Hence DLL4 expressing cells acquire a motile, invasive, sprouting phenotype
8.

Question 11

What is the notch ligand aka

Answer 11

Delta-like ligand 4

Question 12

Which WBC has an important role in vessel anastomosis

Answer 12

Macrophages - they carve out tunnels in the ECM - providing avenues for vessel growth

Question 13

How do macrophages help stabilise newly formed vessels?

Answer 13

By promoting tip cell fusion

Question 14

What 3 processes does stabilising a new blood vessel involve

Answer 14

1. Reforming the endothelial monolayer barrier
2. Recruiting pericytes
3. Switching off active angiogenesis process

Question 15

Which endothelial protein is essential for vessel stability and quiescence?

Answer 15

VE-Cadherin

Cadherin interactions vital in ensuring contact inhibition of cell growth. Cadherins also promote survival of endothelial cells

Question 16

SMC and pericytes are both examples of what type of cells

Answer 16

Mural cells