Tumor Angiogenesis

Question 1

In which 5 situations does angiogenesis occur?

Answer 1

1. Growth and differentiation
2. Wound repair
3. Endometrial and placental growth
4. Retinopathies

Question 2

What are the 4 major stimuli of angiogenesis?

Answer 2

1. VEGF
2. Hypoxia
3. PDGF
4. Angiopoietins

Question 3

Which stimuli is the most potent factor?

Answer 3

VEGF

Question 4

Where does VEGF come from?

Answer 4

Endothelial cells but also many others (stromal, tumors, muscle). Pretty much any cell can produce it.

Question 5

What makes tissue hypoxic?

Answer 5

Lack of oxygen to tissues.

Question 6

Where does PDGF come from?

Answer 6

Mainly from platelets. To a lesser extent from monocytes/macrophages.

Question 7

Where do angiopoietins come from?

Answer 7

Endothelial cells, kidney cells, and pericytes.

Question 8

What does histamine do to vessels?

Answer 8

Increases vascular permeability and vasodilates.

Question 9

How does histamine induce vascular permeability?

Answer 9

Breaks adhesion junctions b/t endothelial cells.

Question 10

Are angiogenic signals present in new capillary formation?

Answer 10

Yes.

Question 11

List the steps of new capillary formation (5).

Answer 11

1. Endothelial cells degrade the vascular basement membrane
2. Endothelial cells migrate, forming tip cells, that migrate toward the stimulus
3. Endothelial cell proliferation forms a lumen
4. The lumen extends towards the angiogenic signals through endothelial cell division and tip cell migration
5. Two “sprouts” fuse their lumens, providing a route for blood flow

Question 12

How do endothelial cells degrade the vascular basement membrane?

Answer 12

They release metalloproteinases.

Question 13

Can endothelial cells invade intact basement membranes?

Answer 13

No.

Question 14

What is notch signaling?

Answer 14

When tip cells migrate first, they then recruit stock cells.

Question 15

The lumen formed by endothelial cell proliferation is also called what?

Answer 15

Folkman’s sprout.

Question 16

Arteriogenesis can alleviate what?

Answer 16

An occluded major artery.

Question 17

In arteriogenesis, are major arterioles recruited?

Answer 17

No.

Question 18

Signifcant vascular remodeling does what in arteriogenesis?

Answer 18

Thickens vascular walls and increases luminal diameter.

Question 19

How is thickening of vascular walls accomplished?

Answer 19

MCP-1 recruits macrophages. Macrophages secrete growth factors which cause endothelial cells and smooth muscle cells to grow (1 layer of endothelium and 2-3 layers of smooth muscle).

Question 20

Is arteriogenesis flow mediated?

Answer 20

Yes: pressure changes and shear stress response stimulate it.

Question 21

What is arteriogenesis?

Answer 21

The expansion of the existing arterial system.

Question 22

T or F. Arteriogenesis and angiogenesis both require the same growth factors and development of lumens.

Answer 22

T.

Question 23

How does angiogenesis differ from arteriogenesis?

Answer 23

The presence of mural cells in angiogenesis. Mural cells are only present on capillaries and not on arteries.

Question 24

Where do heparin and heparan sulfates come from?

Answer 24

Mast cells.

Question 25

What do heparin and heparan sulfates have a high affinity for?

Answer 25

Growth factors.

Question 26

What cell does the binding of PDGF and heparin recruit?

Answer 26

Monocytes.

Question 27

What do angiopoietins do?

Answer 27

Stabilize the process of angiogenesis.

Question 28

What factors stimulate existing endothelial cells?

Answer 28

Proangiogenic factors.

Question 29

Remodeling and growth results in what?

Answer 29

New capillaries.

Question 30

Why must new capillaries recruite pericytes?

Answer 30

To provide protection and stability b/c new capillaries lack smooth muscle cells and are very fragile.

Question 31

Does vascular maturation have to take place in angiogenesis?

Answer 31

Yes.

Question 32

Why does cancer growth depend on angiogenesis?

Answer 32

Cancer cells require oxygen and nutrients.

Question 33

T or F. Inhibiton of angiogenesis inhibits tumor growth but only temporarily.

Answer 33

T.

Question 34

What 2 properties of tumor cells support angiogenesis?

Answer 34

1. Ability to produce growth factors that stimulate endothelial cells in existing capillaries
2. Tumor cells can differentiate into endothelial cells (molecular mimicry)

Question 35

Why are some cancers refractive to anti-VEGF treatment?

Answer 35

Because cells in the neovasculature are mimcs that are not as responsive to VEGF. Tumor cells may exploit other pathways to induce angiogenesis.

Question 36

T or F. Growing tumors will always need a blood supply and will therefore always be undergoing angiogenesis and requiring growth factors.

Answer 36

T.

Question 37

Why is combined anti-VEGF and chemotherapy more effective than monotherapy?

Answer 37

Decreased interstitial pressure allows chemotherapeutic agents access to tumor cells. Otherwise, leakiness leads to diffusion of chemotherapeutic agents. Must normalize the vasculature for proper functioning of agents.

Question 38

What are the 3 current targets of combination therapy development?

Answer 38

1. Anti-angiogenesis
2. Chemotherapeutic agents
3. Anti-lymphangiogenesis

Question 39

What is the goal of anti-angiogenesis therapy?

Answer 39

To starve the tumor and avoid intravasation of metastatic cells.

Question 40

Why is chemotherapy more effective in combination therapy?

Answer 40

Decreased interstitial pressure allows the chemotherapy more access to the tumor.

Question 41

What is the role of anti-lymphangiogenesis therapy in combination therapy?

Answer 41

To maintain chemotherapeutic agent levels and prevent metastases.