Cancer: Angiogenesis Flashcards
Define angiogenesis
The formation of a new blood vessel from pre-existing blood vessels
(There are other ways to make new blood vessels)
Define vasculogenesis
The differentiation of bone marrow progenitor cells (angioblasts) into endothelial cells as the formation of new vascular networks
Define arteriogenesis
Collateral growth and increase in diameter that is dependent on shear stress and external factors e.g. macrophages
Describe sprouting angiogenesis (5 stages)
Growth factors are released in response to hypoxia (most common cause) that activate endothelial cells in small vessels
Endothelial cells undergo a conformational change from a very organised monolayer to sending out filopodia, migrating towards growth factors
Tip cells lead the projection, being pushed by stalk-cells proliferating behind them
One tip cell meets a tip cell from a neighbouring capillary and fuses
Endothelial cells form a bridge and stabilise cell-cell adhesions to create a functioning vessel
Which angiogenesis activator is essential for life?
VEGF
Loss of just one allele is incomaptible with life
The others are less important but developing vasculature still won’t be quite normal without them
What is the transcription factor for hypoxia induced angiogenesis?
HIF (hypoxia-inducible transcription factor)
Which tumour suppressor inhibits HIF under normal conditions?
Von Hippel-Lindau
Name a target of HIF
VEGF gene expression
Name the 5 members of the VEGF family
VEGF-A
VEGF-B
VEGF-C
VEGF-D
PIGF (placental growth factor)
Name the 3 tyrosine kinase receptors for VEGF
VEGFR-1
VEGFR-2
VEGFR-3
Name the 2 coreceptors for VEGF
Nrp1 (neuropilin-1)
Nrp2 (neuropilin-2)
Which VEGFR is the major mediator of VEGF-dependant angiogenesis?
VEGFR-2
Which pathway is responsible for selecting the tip cell?
Canonical Notch signalling pathway
On what cells are Notch receptors present?
Stalk cells
On what cells are Notch ligands present?
And what is the other name for Notch ligand?
Tip cells
Delta-like ligand 4 (Dll4)
How does binding of the Notch ligand to the Notch receptor activate the signalling pathway?
Upon binding, the intracellular domain (NICD) of the notch receptor is clearved
NCID then translocates to the nucleus where it binds to the transcription factor RBP-J and regulates transcription
The stalk cells then begin to divide and push the tip cell towards the growth factor
How does VEGF activation create tip cells?
VEGF activates an endothelial cell in a capillary and leads to an increased expression of Dll4 on its membrane (Notch ligand)
The Notch signalling in the adjacent cells results in decrased expression of VEGFR2 on their surfaces, stopping them from becoming tip cells themselves
How do tip cells and stalk cells sprout forwards through the ECM?
The tip cell is responsible for guidance through the ECM via growth factors (e.g. VEGF and FGFs [fibroblast growth factors])
Macrophages carve the way through the ECM for the subsequent capillary infiltration (both physiolohically and pathalogically), aiding in eventual anastamosis
Briefly describe the process of stabilisation during angiogenesis
It involves reforming the endothelial monolayer barrier
and recruiting pericytes
and switching off the active angiogenesis process
Which adhesion molecule is essential for vessel stabilisation and quiescence?
and what is special about its interaction?
VE-Cadherin. It lines the junctions of endothelial cells
homophilic interaction (binds to the same receptor molecule on adjacent cell)
Note: cadherin interactions are also important in contact inhibition of cell growth
What are mural cells?
The term generally refers to smooth muscle cells and pericytes, both of which are involved in the formation of normal vasculature
(responsive to VEGF)
Why are pericytes so important in stabilisation of new blood vessels?
Because they produce proteins such as antiopoetin 1 (ANG1) which stabilise the endothelium
Which system modulates the activation and quiescence of endothelial cells?
The angiopietin/Tie2 system
What does angiopoetin 1 do?
and where is it released?
Binds to Tie2 and promotes quiescence
Pericytes
What does angiopoeitin 2 do?
and where is it released?
It antagonises ang-1 signalling, and promotes vascular instability and VEGF-dependant angiogenesis
WPB (Weibel-Palade bodies)
Define angiogenic switch
The key point in tumour development where the tumour gets to a certain size so that diffusion is no longer sufficient, and some cells within the tumour become hypoxic and send angiogenic signals
Name 5 characteristics of tumour blood vessels resulting from pathalogical angiogenesis
Irregularly shaped
Not organised into definitive venules, arterioles and capillaries
Leaky and haemorrhagic
Perivascular cells often become loosely associated
Some may recruit endothelial progenitor cells from the bone marrow
Why must anti-angiogenic drugs be balanced as to not be too aggressive?
It may damage healthy vasculature leading to the tumour, meaning inadequate delivery of further drugs
and oxygen which leads to hypoxia, causing the release of VEGF etc. which actively reverses the effects of the treatment you just prescribed
What is avastin?
is it effective in cancer therapy?
An anti-VEGF humanised MAb (mouse antibody)
There are no survival advantages over chemotherapy alone
There are many significant side-effects because VEGF is essential for the homeostasis of the endothelium
What was avastin eventually used to treat (being rebranded to lucentis)
Age-related macular degeneration (AMD)
What might anti-angiogenic therapy later be used for? (4)
Combination therapy with other anti-cancer therapies
Combinatorial strategies with drugs targeting resistance mechanisms to anti-angiogenics
Novel non-VEGF targets
Pro-angiogenic therapy in ischemia, vascular repair and tissue engineering
