Angiogenesis

Question 1

What is angiogenesis versus vasculogenesis?

Answer 1

1. Angiogenesis - Branching of existing vessels
2. Vasculogenesis - Creation of brand new vessels from scratch

Question 2

Steps for angiogenesis

Answer 2

1. Growth factor stimulation leads to endothelial detachment
2. Stalk cell serves as root for new endothelial cell growth (sprout)
3. Tip cells proliferate out from stalk cell to form new endothelium

Question 3

What are the two types of cell necessary for making up a blood vessel?

Answer 3

1. Endothelial cell - Vessel boundary
2. Smooth muscle - Wraps around the endothelial cells for vessel tone

Question 4

Role of hypoxia in angiogenesis

Answer 4

• Tumor needs nutrients and oxygen to increase biomass
• Initially tumor will be in a hypoxic state while trying to proliferate
• EGF pathway stimulates VEGF generation leading to angiogenesis

Question 5

Why do tumors need vascularization?

Answer 5

1. Oxygen
2. Nutrients
3. Removal of waste
4. Prevent acidic environment

Question 6

How does the organization of tumor vasculature compare to standard vasculature?

Answer 6

• Standard: Very organized, straight capillary beds
• Tumor: Chaotic, leaky

Question 7

What are potential benefits of having leaky vaculature/lymphatics for a tumor?

Answer 7

Provides opportunities for tumors to metastasize, lymphatic leaks allow for decompression of pressure

Question 8

What is the angiogenic switch?

Answer 8

• Capillary development in a tumor has delayed evelopment and only a small fraction of hyperplastic islets actually develop agiogenic islets
• Believed to be thought of due to matrix metalloprotease-9 activation to stimulate VEGF

Question 9

What is the homeostatic model of angiogenesis?

Answer 9

• Prinicple that angiogenesis is a balance between activating and inhibition factors
• Activators: VEGF-A, VEGF-B/C, FGF1, FGF2, etc.
• Inhibitors: Thrombospondin-1,2, Interferon A/B, Angiostatin, Endostatin, Collagen IV Fragments etc.

Question 10

What is VEGF?

Answer 10

• Discovered as a potent vascular permeability factor, 50,000 times more potent than histamine
• Plays roles in cell proliferation, vascular permeability, cell migration, remodeling, kinase activty and vasculogenesis/angiogenesis

Question 11

What are the different types of VEGF receptors?

Answer 11

1. VEGFR2 - Primary cascade that is best studied
2. VEGFR3 - Major role in vasculogenesis/lymphanogenesis
3. VEGFR1 - Least understood, purpose not determined yet

Question 12

What is Notch?

Answer 12

• Transmembrane protein used for cell-cell messaging
• Extracellular domain is cleaved which causes intracellular entry

Question 13

What are advantages of anti-angiogenic therapy?

Answer 13

1. Targeting a genetically stable population (endothelial cells) instead of a genetically unstable one (tumor cells)
2. Therapy involves naturally occurring preins in the body - High tolerance/less side effects
3. Easy accessibility for drugs - Circulatory system
4. Target metastasis at origin

Question 14

What are some different strategies to target VEGF?

Answer 14

1. Anti-VEGF antibodies
2. Soluble VEGF receptors - Higher affinity than VEGF Ab
3. Aptamers - Small molecule VEGF inhibitors, horribly toxic

Question 15

What other disease are anti-VEGF antibodies used to treat now?

Answer 15

Wet Macular Degeneration

Question 16

What is a common combination target with VEGF?

Answer 16

• Smooth muscle (pericyte) targeting via PDGF receptors
• Increases susceptibity to VEGF-R inhibition

Question 17

What are mechanisms of resistance to anti-angiogenic therapy?

Answer 17