Chapter 11

Question 1

Which VEGF and VEGFR are most responsible for the angiogenic response in normal angiogenesis?

Answer 1

VEGF-A on VEGFR2

Question 2

What is the result of increased VEGF?

Answer 2

1- Dilatation and formation of a mother vessel

2- Detachment of the mural cells

3- Upregulattion of Angiopoientin 2 which inactivate Tie-2 = reduced pericyte and endothelial cell contact resulting in liberated endothelial cells

4. formation of VEGF sensing endothelial sprouts which contain VEGFR2 receptors
5. The sporout cell will follow VEGF gradient

Question 3

Which VEGFs are mainly responsible for lymphangiogenesis?

Answer 3

VEGF C/D

Question 4

By which 3 mechanisms may angiogenesis occur? and which one is most common cancer?

Answer 4

Intussusception, vascular splitting, sprouting, the latter is the main form in cancer

Question 5

How is angiogenesis initiated in a tumour?

Answer 5

A precapillary vessel is exposed to a gradient of proangiogenic substances - such as VEGF expression induced by hypoxia.

Question 6

Which cellular signalling pathway is important in angiogenesis?

Answer 6

The notch pathway

Question 7

How are proteinases involved in normal angiogenesis?

Answer 7

MMPs are important for liberating endothelial cells by dissolving the capillary basement membrane and release agnigeic factors from the ECM store.

Question 8

What is vascular cooption?

Answer 8

When cancer cells exploit pre-existing vasculature by grown around and eveloping the vessel. Will however result after time in blood vessel regression and thrombosis

Question 9

Which effect does VEGF-A have on endothelial cell?

Answer 9

Promote angiogenesis, is a potent mitogen, stimulate mobility and survival and chemoattractant for EC progenitor cells

Question 10

What is the main effect of PDGF in angiogenesis?

Answer 10

Vascular maturation

Question 11

What is the main function of angiopoietins and their binding to TIE receptors?

Answer 11

They mediate EC survival, vascular permeability and recruitment of mural cells

Question 12

What happens when angiopoietin expression is high, but VEGF is low?

Answer 12

It does not promote vascular sprouting without VEGF and will result in promotion of vascular regression.

Question 13

Name the most important factors stimulating angiogenesis?

Answer 13

VEGF, PlGF, FGF1/2, HGF, IL-8 - these factors works directly on Ecstatics
TGF alpha, beta, and other cytokines may also stimulate angiogenesis indirectly by promote release and production of the factors above.

Question 14

Name the most important inhibitors of angiogenesis?

Answer 14

Thrombospondins 1 and 2, fragments of coagulation related chemockines, and hormones, cytokines (INF)

Question 15

Which cytokines is known to inhibit tumor angiogenesis?

Answer 15

Interferon alpha, beta and gamma

Question 16

What is the target for the majority of antiangiognic drugs used today?

Answer 16

VEGF or VEGFR

Question 17

Which mechanisms will trigger tumour neovascularisation?

Answer 17

The preangiogenic phase is defined by hypoxia and lack of macromolecules, and the cells ability to survive such conditions. Beyond perivascular diffusion the cancer cells will either undergo growth arrest or enter a state of dormancy. Exposure to these conditions can drive the onset of angiogenesis.

Question 18

Aggiogenesis is often attributed to the agnigeic switch- how does cancer cells “turn on” angiogenesis?

Answer 18

1. directly by production of angiogenic factors

2. by causing hypoxic shift in the microenvironment, recruit stromal cells and induce inflammation

Question 19

How does hypoxia trigger angiogenesis?

Answer 19

Hypoxia induce HIF-1/2 expression, and his have several angiogenesis related targets in its pathway including VEGF, SDF1, ANG2, PlGF, PFGF, stew cell factor and VEGEFR1. It also lead to down regulation of angiogenesis inhibitors such as thrombospondin 1

Question 20

Cancer cells can express proangiogenic properties also without hypoxia, which ones?

Answer 20

VEGF, Ras, Src, Myc, EGFR, HER2, i addition to loss of function affecting p53, PTEN, p16 and VHL

Question 21

What is the result of oncogenic mutations on angiogenesis?

Answer 21

1) Upregulation of vascular stimulators such as VEGF, FGF, IL-6, IL-8 and ANG-1 and downregulation of inhibitory factors such as TSP, endostatin and tumstatin.

Question 22

How is tumour angiogenesis affected by inflammation?

Answer 22

The inflammation can be initiated by infection, immunactivation, oncogenic mutations or the microenvironment, result in recruitment of inflammatory cells such as macrophages and myeloid cells- these produce proteolytic enzymes, pro-angiogenic growth factors, cytokines and chemokine eg. VEGF-A and IL-8

Question 23

Which main factors can initiate tumour angiogenesis?

Answer 23

Hypoxia 
Lack of nutrients and macromolecules
Ongenic mutations
Inflammation
Tumour stromal cells

Question 24

which other factors impact tumour angiogenesis?

Answer 24

1. Genetic polymorphism of the host
2. Age of the host

Others include the tumour microcirculation itself, lymphatic drainage and CSC

Question 25

Which antiangiogenic drugs target VEGF?

Answer 25

Bevacizymab- colorectal cancer

Question 26

Which antiangiogenic drugs target VEGFR?

Answer 26

Sunitinib-

Sorafenib-

Question 27

What is the MAO for thalidomide?

Answer 27

it inhibits angiogenesis through inflammatory pathways- a small molecule. Uses in MM

Question 28

Which oncogenes stimulate tumour angiogenesis?

Answer 28

HER-2 (ERBB2), EFGR, RAS

Question 29

Name 4 main strategies to target tumour angiogenesis and an example of drug developed for inhibition?

Answer 29

1. Targeting oncopathways such as EGFR, HER-2, Myc, sir - drug example; trastuzumab

Question 30

Which factors are involved in the angiogenic switch?

Answer 30

Pre-agniogenic: overweight antiangiogenic factors- TSP-1, PEDF, PED
Angiogenic: VEGF expression outweigh the antiangiogenic factors

Question 31

Name 2 non-angiogenic mechanisms tumour cells use for to access vasculature?

Answer 31

1. Vascular cooption

2. Vasulogenic mimicry

Question 32

How can cancer cells influence or initiate angiogenesis?

Answer 32

1. Produce proangiogenic factors
2. Indirectly through the shift in tissue microenvironent resulting in recruitment of proangigoenic stromal cells
3. Induce inflammatory response

Question 33

Name 5 stimulatory factors involved in tumour angiogenesis?

Answer 33

FGF
IL-8
IL-6
TNF-alpha
MMP9

Question 34

Explain the angiogenic switch?

Answer 34

When tumour induced signalling result in net stimulatory activity overriding the inhibitory mechanisms initiation angiogenesis.

Question 35

How can tumours induce angiogenesis?

Answer 35

1. Directly through mutations in oncogenes and tumour suppressor genes, alteration in the mediations of the angiogenic switch
2. Indirectly
   - hypoxia
   - inflammation
   - recruitment of stromal cells
   - PLT / coagulation factors

Question 36

How does hypoxia influence angiogenesis?

Answer 36

1. Induce HIF- transcription factor for VEGF, CXCL12, ANG2, PDGF and inhibitory for TSP-1
2. Induce localised VEGF production
3. Stimulate arteriogenesis via NO resulting in feeding vessel development

Question 37

How does inflammation stimulation angiogenesis?

Answer 37

1. Recruit tumour macrophages which produce VEGF-A and IL-8

Question 38

.How does tumour associated stromal cells influence angiogenesis?

Answer 38

Produce VEGF A

Question 39

How does platelet and coagulation stimulate angiogenesis?

Answer 39

Thrombin, thomboplastin and platelet increase VEGF and IL-8