Angiogenesis Flashcards
What is angiogenesis versus vasculogenesis?
- Angiogenesis - Branching of existing vessels
- Vasculogenesis - Creation of brand new vessels from scratch
Steps for angiogenesis
- Growth factor stimulation leads to endothelial detachment
- Stalk cell serves as root for new endothelial cell growth (sprout)
- Tip cells proliferate out from stalk cell to form new endothelium
What are the two types of cell necessary for making up a blood vessel?
- Endothelial cell - Vessel boundary
- Smooth muscle - Wraps around the endothelial cells for vessel tone
Role of hypoxia in angiogenesis
- 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
Why do tumors need vascularization?
- Oxygen
- Nutrients
- Removal of waste
- Prevent acidic environment
How does the organization of tumor vasculature compare to standard vasculature?
- Standard: Very organized, straight capillary beds
- Tumor: Chaotic, leaky
What are potential benefits of having leaky vaculature/lymphatics for a tumor?
Provides opportunities for tumors to metastasize, lymphatic leaks allow for decompression of pressure
What is the angiogenic switch?
- 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
What is the homeostatic model of angiogenesis?
- 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.
What is VEGF?
- 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
What are the different types of VEGF receptors?
- VEGFR2 - Primary cascade that is best studied
- VEGFR3 - Major role in vasculogenesis/lymphanogenesis
- VEGFR1 - Least understood, purpose not determined yet
What is Notch?
- Transmembrane protein used for cell-cell messaging
- Extracellular domain is cleaved which causes intracellular entry
What are advantages of anti-angiogenic therapy?
- Targeting a genetically stable population (endothelial cells) instead of a genetically unstable one (tumor cells)
- Therapy involves naturally occurring preins in the body - High tolerance/less side effects
- Easy accessibility for drugs - Circulatory system
- Target metastasis at origin
What are some different strategies to target VEGF?
- Anti-VEGF antibodies
- Soluble VEGF receptors - Higher affinity than VEGF Ab
- Aptamers - Small molecule VEGF inhibitors, horribly toxic
What other disease are anti-VEGF antibodies used to treat now?
Wet Macular Degeneration
What are mechanisms of resistance to anti-angiogenic therapy?
