CANCER- angiogenesis Flashcards
what does angiogenesis mean?
formation of new blood vessels
what triggers the release of angiogenic factors?
hypoxia
what are the inhibitors of angiogenesis?
extracellular matrix:
thrombospondin-1
angiostatin
endostatin
soluble factors: sVEGF-R IL-10 IL-12 TNF-a
avB3- receptor
whjat are the activators of angiogenesis?
GF: VEGF family FGF family TGF beta PDGF
soluble factors:
IL-6
factor XIII
TNF- a
cell surface receptor avB3
outline the multistep process of sprouting angiogenesis
- tip/stalk cell selection;
- tip cell navigation and
stalk cell proliferation; - branching coordination;
- stalk elongation, tip cell
fusion, and lumen
formation; - perfusion and vessel
maturation.
what happens in the absence of oxygen?
the HIF-a does not bind to the von hippel-lindau protein. HIF goes into the nucleus, binds to the DNA that codes for the gene responsible for angiogenesis
what does VEGF bind to?
it binds to a cell on the vessel and turns it into a tip cell.
by doing this it tells the surrounding cells to become stalk cells and support the tip cell
what is tip cell selection regulated by?
the Notch pathway
what is the Notch pathway?
essential for development and basic functioning of cells
ligand and receptor on two different cells bind
this binding causes the cleavage of the intercellular domain of notch
this can go into the nucleus and binds to the transcription factor RBP-J
when might angiogenesis occur?
embryonic development, wound healing and in the menstrual cycle.
what controls gene regulation?
HIF – Hypoxia-Inducible Transcription Factor
what controls levels of HIF
pVHL – protein Von Hippel-Lindau tumour suppressor gene
what happens in the presence of oxygen in relation to HIF and pVHL?
pVHL adds a hydroxyproline group to HIF and HIF is degraded by a proteasome.
what are the 5 families of VEGF?
VEGF-A/B/C/D and Placental GF (PlGF)
what are the TK receptors?
VEGFR-1/2/3; and co-receptors neuropilin (Nrp1, Nrp2)
what is required for the angiogenic sprouting outgrowth and guidance?
- Myeloid cells are recruited to support and guide the sprout (stimulated by Ang-II).
- Macrophages have a large role in angiogenesis anastomosis:
o Macrophages carve out tunnels in the ECM for subsequent capillary infiltration.
o Tissue-resident macrophages associate with the tip-cells during anastomosis to support the structure.
what is the importance of platelets in angiogenesis?
full of regulators of angiogenesis, both inhibitory and stimulatory
what controls contact inhibition?
the tight junctions and adherens
what cells are important for the stability of blood neovessels
mural cells (pericytes) which surround the capillary cells
what do the mural cells produce?
angiopoietin 1 which promotes survival, anti inflammation and tight junctions
the signalling pathway uses the angiopoietin-Tie 2 ligand receptor system
what is angiogenesis driven by?
PIP cells and VEGF
what is an anti VEGF drug? and how is it effective?
avastin
blocking the VEGF pathway means it blocks tumour angiogenesis so the tumour cannot get the nutrients it requires to grow
what is the angiogenic switch?
up to a certain size tumour cells can grow and survive without vasculature as they can get their requirements from the surrounding environment
but there is a point above which tumours require their own vessel network- this is the angiogenic switch
tumours release angiogenic factors
-eg VEGF
so they can grow.
how are tumour blood vessels different?
irregularly shaped dilated tortuous not organised into definitive venuoles leaky and haemorrhagic
give examples of some pro angiogenic growth factors that cancer associated fibroblasts secrete
VEGFA
FGF2
CXCL12
PDGFC
what are the side effects of avastin?
GI perforation hypertension proteinuria venous thrombosis haemorrhage wound healing complications
why is avastin not as effective as anticipated?
VEFG is essential not only for angiogenesis but also for endothelial survival
what are the potential mechanisms of resistance to anti-VEGF therapy in cancer?
by blocking the tumour vasculature it causes hypoxia which may stimulate the tumour to release other angiogenic factors or increase tumour invasiveness
tumour vessels may be less sensitive to VEGF inhibition due to vessel lining by tumour cells
