Cancer 7: Angiogenesis Flashcards
What is angiogenesis?
Cascade of events leading to the formation of new blood vessels-happens where endothelium is thin and can form sprouting vessels
usually triggered by need for oxygen which leads to production of VEGF
This activates endothelial cells and changes them to proliferate and migrate towards the place where oxygen is needed
Happens a lot in cancer
Not all blood vessels are the same-and angiogenic events are also different in wound or embryos
Also arteriogenesis and vasculogenesis exist
WHat is angiogenesis a balance of?
numerous inhbitors in ECM-thromspondin , angiostatin, endostatin, soluble factors, cell surface receptors
Acvtivators-VEGFm FGF, THF, soluble IL8, TNFa
Some are essenstial (VEGF) and some are more for modulation (VWF)
Some can be both inhbitory and activatory
always crucial: Maturation and integrity of the vessels-once the vessel is initiated it has to be stabilised (VE-Cadherins, Angiopeotin, ERG, platelets
Describe the step by step angiogenesis process
Endothelial activation-determines by which cell gets the GF
That cell becomes the tip cell and the ones around become the stalk cells
Sprouting from the tip-navigate and stalk proliferates
COordination of branching , continouis elongation and then lumen formation (when two tips meet and extend towards one another
Then maturation
How does hypoxia trigger angiogenesis?
Hypoxia is most common cause of formation
uses HIG-hypoxia inducible TF–inhbited in presence of oxygen (Von-Hippel Lindau factor binds and inhbits it)
When hypoxia, protiens detatch and HIF form complex, which activated genes including VEGF
How Receptors does VEGF bind?
5 forms of VEGF-VEGFA-D and placental GF
3 tyrosine kinase (dimerise)(VEGF1-3)-and co receptors neuropilin
Some cells have different receptors-different assemblies of receptors cause different effects in different cells
The decision of the TIP cell happens with VEGFR2-
The tip is what then decides that cells around it are stalk cells
How is the tip cell determined and what does it do?
The decision of the TIP cell happens with VEGFR2-produced by anyother cell around it that decides its in lack of O2 (like a macrophage or other)
The tip is what then decides that cells around it are stalk cells
selection is based on the notch pathway-
notch Ligand and receptor -cell surface molecule
The binding causes cleavage of intracellular domain of notch receptor-release the inner part which become a TF and activate DNA expression
So usually Tip cell expresses the ligand and the notch receptor on the stalk cell
which one VEGF binds too seems random
How does angiogenesis progress after the tip and stalk cells have been selected? What cells are involved
Extension and lumen formation-carve the tunnel-can meet halfway with other side-many other cells now
Myeloid cells support sprouting-macrophages help carve little tunnels for the endothelial cells to go through
Wrap around the tip cells
Platelets–play a role in heamostasis but also have a role in angiogenesis-both pro and anti factors
What is the final step of angiogenesis?
maturation and consolidation of the new vessel-
Need to form endothelial junction-tight junctions and adherens junctions–the control of these junction are crucial and modulated by VEGF
other part that is crucial is pericyte maturation-wrap aroun the cappilary cells-mysterious cell-unsure where it comes from but ressemble SMC–wrap all around the vessel
They produce essential molecules helping stability-angiopoetin pathway
Bins sTie2 receptor (nearly only on endothelial)-produce Ang1 in quiescent endothelial cell-produced by pericytes
Ang2 is released during angiogenesis by other endothelial cells-promotes vascular instability and VEGF dependent angiogenesis-modulates
Ang2 is compeiting with Ang1 for Tie receptor
How does angiogenesis relate to cancer (basic concepto)
As tumours grow, up to a certain size it cna grow with nutrients around]
but after a point, it needs more nutrients and starts driving angiogensis
But doesnt fully produce all the factors-produce a lot of VEGF
different tumours have different abilites to lead angiogenesis
How are tumours blood vessels different from nromal ones? Why?
irregularly shape, dilated,
Not organised in definitive arteries, veins, etc
often leaky and heamorrhagic
Pericytes are loosly associated
Cancer vasculature cannot be blocked normally because different pathway
Cancer associated fibroblasts-help angiogensis
But cancer cells still dont produce the right molecules
Pericytes only loosely activated
Platelets go to cancers a lot because heammorrhagic-pro-angiogensis but also pro-thrombotic
Whata re the therapeutic targets to inhbit VEGF? What is a good exemple?
Antibodies targetting either VEGF directly or the VEGFR
Also molecules that block signalling downstream of the receptor
Lot of animal studies show that VEGF blocking inhbits the formation of the tumour
Human mAB Anti-VEGF-Avastin–curently in use for numerous cancer (like cervicalm colorectal)-
But not great-after a few years-no beter survival to chemo
No quality of live advantage
Benefits are transitory as tumours becomes resistant
and many side effects
Why do tumour cells become anti-VEGF resistant?
As you block VEGF, possible that hypoxia lead to production of other factors leading to angiogenesis
Maybe tumour vessels are less sensitive to VEGF inhbition due to weird lining
Maybe tumour cells that recruit pericytes are less responsive to VEGF inhbition
Its been shown that tumorus undergo to be vasculogenetic mimicry-tumour cells pretend to be endothelial cell and let blood go through them-no need for VEGF
SO need to balance-not too much for tumour to become hypoxic, and let blood reach it to have chemo arrive
but block enough to stop the tumour
How is the future of angiogenesis blocking for tumour looking like?
Using RNAseq-try and find new targets everyday (comparing tumours to normal tissue)
Especially vasculature genes seem very different-lot of many targets outt here
To find the better targets/strategies, need good in vitro models-and cultures arent perfect-so 3D printed organ “organs on a chip”-better model
3D phenotype cells is very different than 2D
Make tumour on a cell-vessels can grow in it, then add tumour and they grow and then can use drugs to see if they work
How can anti-angiogenic therapy help with other diseases? Exemple?
Well extra angiogensis is present in alot other disease
Age-related macular degeneration has a lot of angiogensis-leading to oedema which causes vision loss
no treatment before avastin-worked very vell-first cure ever
