Neoplasia VI: Angiogenesis and Metastasis Flashcards
Continuous capillaries
Have tight occluding junctions that seal the spaces between endothelial cells. Transport must take place across membranes.
Fenestrated Capillaries
Have perforations (fenestrations) through endothelial cells that allow for exchange of small molecules with blood
Sinusoid Capillaries
Wide gap between endothelial cells, fenestrations, and a discontinuous basement membrane that allows for exchange of macromolecules and cells with tissue and blood
VEGF AND bFGF
- Receptors display on surface of endothelial cells
- Stimulate endothelial cell proliferation
Production of VEGF
- Governed by availability of oxygen
- Activation:HIF-1a senses hypoxia–>HIF-1b binds to HIF-1a, activates VEGF and transcription can go
- Deactivation: Proline hydroxylase hydroxylzes HIF-1a–>pHVL and two other proteins recognize and bind, polyubiquitylation, and degradation
Steps in formation of new capillaries
- Stimulation of endothelial cells by angiogenic GF’s
- Degradation of parental basal lamina by activated endothelial cells to facilitate formation of capillary spout
- Endothelial cell migration and proliferation
- Maturation of endothelial cells involving the formation of capillary tubes, reformation of basal lamina and recruitment of pericytes
Cells of the vasculature
endothelial, perictyes, smooth muscle
Nonvascular cells
neoplastic cells, supporting cells of the stroma
Step 1 in angiogenesis
stimulation of endothelial cells by GF’s
- VEGF and bFGF
Step 2 in Angiogenesis
Degredation of capillary basal lamina by activated endothelial cells
- Secreted Proteases:
- Matrix metalloproteases (MMP’s)
- Plasminogen activator urokinase (uPA)
Step 3 in Angiogenesis
Capillary sprout formation and migration of endothelial cells
- Regulation of cell migration
- Integrins
- extracellular proteases
Step 4 of Angiogenesis
New Vessel Maturation
- Angiopoeitin 1 (ANG-1)
- Platelet derived growth factor (PDGF)
Activators of Angiogenesis
- VEGF-A,B,C
- FGF1(aFGF)
- FGF2(bFGF)
- other FGF’s
Inhibitors of Angiogenesis
- Thrombospondin 1,2
- Interferon a,b
- angiostatin
- endostatin
- collagen IV fragments
MMP9
From mast cells and macrophages in bone marrow
- release VEGF that is sequestered in extracellular matrix