Angiogenesis Flashcards
Hemangioblast
- Link hematopoietic and vascular systems during embryonic development producing hematopoietic stem cells and angioblasts
Angioblasts
- Endothelial cell precursors in vasculogenesis
- Proliferate and migrate to peripheral sites and differentiate into endothelial cells that form arteries, veins and lymphatics, pericytes and smooth muscle cells
Angioblast like cells
- Stored in adult bone marrow
- Recruited to tissue to initiate angiogenesis
- Express markers for hematopoietic stem cells and endothelial specific markers
- Participate in replacement of lost endothelial cells, reendothelization of vascular implants, cutaneous wounds and tumors
VEGF
- At the center of the angiogenic pathway
- Increases vascular permeability during angiogenesis
- Secreted by mesenchymal and stromal cells
- Stimulates vascular endothelial cell growth, survival and proliferation
FGF-2
- Enhances endothelial proliferation, differentiation and migration towards angiocentric stimulus
Angiopoietins 1 and 2, PDGF, TGF beta
- Participate in blood vessel stabilization
Ang 1
- Interacts w/receptor on endothelial cells called Tie 2 to recruit periendothelial cells
PDGF
- Recruits smooth muscle cells
TGF beta
- Stabilized newly formed vessels
Ang1/Tie2
- Mediates vessel maturation and maintains endothelial quiescence; meaning its going to dampen down the proliferative process
Ang2/Tie2
- Loosens endothelial cells making them more responsive to VEGF and inhibitors of angiogenesis
Form and maintains new blood vessels
- Integrin
Matricellular proteins
- Destabilize cell matrix interactions and promote angiogenesis
Proteinases
- Plasminogen activator and metalloproteinases remodel tissues during endothelial invasion, also release VEGF, FGF-2
Newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting
- Growth factors and PDGF
Tumor vessels irregularly shaped and lead due to increased levels of
- VEGF
Tumors often have high levels of
- VEGF and FGF
“Angiogenic Switch” regulators
- Activators: VEGF, FGF, IL-8
- Inhibitors: thrombospondin-1, angiostatin, interferon-alpha/beta)
Environment and cellular triggers that induce VEGF pathway
- Hypoxia
*gene expression of VEGF is upregulated in response to hypoxic conditions
- Oncogenes
*oncogenes and tumor suppressor genes are assoc. w/increased VEGF production
- Cellular receptors
*EGFR, HER-2, IGF-1R activation or overexpression
- Other growth factors and cytokines
*COX-2, PDGF
VEGF-1
- Crucial to embryonic angiogenesis
- Does not appear to be critical in pathogenic angiogenesis
VEGFR-2
- Tyrosine kinase receptor present on endothelial cells and their precursors
*expressed on tumor cells as well
- Mediates proliferation, migration, survival and angiogenesis
- VEGF and VEGFR-2 stimulate endothelial cell precursors from bone marrow, increase proliferation of the cells at site of angiogenesis
- Most important VEGF receptor in tumor angiogenesis
- Mediates the majority of VEGF angiogenic effects
VEGFR-3
- Found only in lymphatic endothelial cells
- Assoc. w/lymph node metastasis
- Effects mainly in lymphatic cells
VEGF and cancer
- Increases interstitial pressure
*high interstital pressure may imped delivery of therapeutic agents to tumors
- May prevent immune response to tumors
- Continuously expressed throughout the entire tumor life cycle
- Direct and continuous VEFG inhibition is an important antitumor strategy
- Potent and predominant factor in metastasis of tumors
- Can prevent functional maturation of dendritic cells
- VEGF overexpression has been assoc. w/poor prognosis in a variety of solid tumor types
