7: Angiogenesis Flashcards
How do you call different forms of new vascular formation?
How do they differ?
- Vasculargenesis
- in emberyological development –> from bone marrow progenitor cells
- Ateriogenesis
- collateral growth
- Antiogenesis
- sprouting of blood vessels, important in adult life and tumor development
Explain the overall concept of regulation of angiogenesis
Regulated by many proteins:
- Some molecules are essential (i.e. VEGF), other are required for modulation (i.e. VWF)
- Many are best known for other functions (i.e. TNF-a, VWF)
- Factors can have both: pro and anti-angiogenic effects
Explain the role of Hypoxia in Angiogenesis
Hypoxia is a powerful stimulus that triggers antiogenesis
- In presence of oxygen: HIF release is inhibited by pVHL: Von Hippel–Lindau tumor
- Hypoxia causes release of HIF (hypoxia-inducible transcription factor)
- –> HIF triggers VEGF release and other Growth factors
Explain the release of VEGF?
Often released due to Hypoxia:
In presence of oxygen: HIF release is inhibited by pVHL: Von Hippel–Lindau tumor
Hypoxia causes release of HIF (hypoxia-inducible transcription factor)
–> HIF triggers VEGF release and other Growth factors
How many forms of VEGF are there?
To which receptors do they bind?
There a 5 different VEGF (Vascular Endothelial Growth Factor)
- VEGF A-D
- PIGF (Placental Growth Factor)
- Bind to thyrosine kinase receptors: VEGF receptors 1-3
Which receptor and signaling molecule is mainly incvolvedn in angiogenesis?
•VEGFR-2 is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival, proliferation.
How does VGEF activate angiogenesis?
Binds to receptor on one cell that becomes the tip cell
- also gives direction of antiogenesis: vessesl sprout towards the VEGF gradient
What is the tip cell in angiogenesis?
Tip cell is the top cell that gives direction for cell growth –>signals to surrounding cells, thex become the stalk cells
Which signals activate the tip cell?
What happens upon activation?
DLL4 and JAGGED
Processes that enable cell migration take place:
- degradation of the basement membrane
- loss of connections to adjacent endothelial cells (junctions and perycyte detachents)
- matrix remodeling and
- increased permeability
What are the stalk cells?
How do they get activated?
Stalk cells are the cells next to the endothelia tip cells
- get activated via the Notch system
- Notch ligand on tip cell activates the Notch receptor on stalk cell
- this sets of the production of notch intracellular domain (NICD)
- NICD is brought to nucleus where it activates transcription factors RBP-J
Explain the cellular process of the tip cell selection
- In stable blood vessels, Dll4 and Notch signalling maintain quiescence
- VEGF increases expression of Dll4 (Tip Cell)
- –> Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
- Tip-cell phenotype by Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
- Adjacent cells forms Stalk cells
What is the function of the stalk cell?
form the base of the emerging sprout, proliferate to support sprout elongation.
How do tip cells move and lead the path to angiogenesis?
They navigate in response to guidance signals
Adhere to Extracellular Matrix to migrate
Stalk cells behind the tip cell proliferate, elongate and form a lumen, and sprouts of tip cells fuse to establish a perfused neovessel.
Explain the role of macrophages in angiogenesis
Important in angiogenesis (physiologically and pathologically)
- •Macrophages carve out tunnels in the extra cellular matrix (ECM), providing avenues for capillary infiltration
•Tissue-resident macrophages can be associated with angiogenic tip cells during anastomosis
Explain the role of platelets in angiogenesis
They are both: pro-angiogenic and anti-angiogenic and involved in physiolgical and pathological angiogenesis
What happens during stabelisation and quiescence of newly formed vessels?
- Lumen formation allows perfusion of neovessels (possible after fusion of neighboring branches)
- Stabelisation of new vessel via
- re-establishing junctions
- deposition of basement membrane
- maturation of pericytes
- production of vascular maintenance signals
Explain the role and regulation of tight junctions and adherence junctions in endothelial cells in angiogenesis
Very important to restore connections and Barrier formations during stabelisation of neovessel:
Mainly regulated via VE-cadherin
- Constitutively expressed at junctions
- mediates adhesion between endothelial cells and intracellular signalling
- Controls contact inhibition of cell growth
- Promotes survival of EC
Explain the role of pericyte maturation in senscence of neovessels in angiogenesis
Mural cells (pericytes) help to stabilise the neovessels by modulation of the:
via the Angiopoietin/Tie-2 system
What is the Angiopoietin-Tie2 ligand-receptor system?
What is its role?
Pathway that is invoved in an intracellular siganling pathway that controls stability of neovessels in angiogenesis
Explain the role of Ang-1 in angiogenesis
How is it released?
Ang-1 is an agonist of the Tie 2 receptor, importnat in stabelising of neovessels
- when bindin to it
- promotes vessel stability
- reduces inflammatory gene expression
Released by the pericytes
Explain the role and release of Ang-2 in angiogenesis
It is released upon inflammatory stimmuli and antagonises the Tie2 receptor
- blocks the effects of Ang-1:
- increases vascular instability
- promotes VEGF dependant angiogenesis
Summarise the process of angiogenesis
When does a tumor needs vessels?
Needs vessels when it becomes larger than 1mm3
How do tumors induce angiogenesis?
Tumor secretes angiogenic that stimmulate angiogenesis to tumor of adjacent vessels:
–> dependant on the hosts vasculature
What is meant by the term the angeiogenic switch?
What happes there?
It is the initiation of angiogenesis in a tumor cell
- mostly a hypoxia induced release of angiogenic factors leading to
- angiogenesis ( perivascular detachment and vessel dilation (b), followed by angiogenic sprouting (c), new vessel formation and maturation, and the recruitment of perivascular cells (d))
What are the characteristics of tumor blood vessels?
Tumour blood vessels
- irregularly shaped, dilated, tortuous
- not organized into definitive venules, arterioles and capillaries
- leaky and haemorrhagic, partly due to the overproduction of VEGF
- perivascular cells often become loosely associated
–> not like a normal vessel!
Why do tumor vesseld differ from normal vessels?
Because they don’t have all the Factors involved in angiogenesis available
–> might only have a few so e.g. can’t stabelise as well or have overexpresseion of other factors (e..g VEGF)
Which other cells (other than the actual cancer cells) are involved in tumor angiogenesis?
- Cancer-associated fibroblasts
- Pericytes
- Platelets
What is the role of Cance-associated Fibroblasts in angiogenesis of cancer cells?
secrete extracellular matrix; pro-angiogenic growth factors,
Explain the role of pericytes in tumor angiogenesis
Pericytes are loosely associated with with tumour-associated blood vessels (TABVs), and this favours chronic leakage in tumours. This is enhanced by angiopoietin 2 (ANGPT2)
Explain the role of platelets in tumor angiogenesis
Overall: pro-angiogenic
Tumors cause platelet activation leading to
- release of pro-angiogenic factors (VEGFA, platelet-derived growth factors (PDGFs), FGF2)
- some antiostatic molecules, but tend to play a minro roll
How can the VEGF pathway be therapeutically be exploited in cancer treatment?
It is often highly expressed in Cancer:
- might be inhibited to inhibits tumor angiogenesis –> Avastin (Bevacizumab)
What are the limitations and side-effects in the use of Avastin (Bevacizumab)
Side effects:
GI perforation, Hypertension, Proteinuria, Venous thrombosis, Haemorrage, Wound healing complications –> because it is needed in Endothelial survival
But also just has limited effects on survival rate and quality of life
What are the potential mechanisms of resistance of tumor cells agaisnt anti-VEGF therapy?
- Other hypoxia induced growth factors might be produced by tumor
- Tumours vessels maybe less sensitive to VEGF inhibition due to vessel lining by tumour cells or endothelial cells derived from tumours
- Tumour cells that recruit pericytes maybe less responsive to VEGF therapy
What is the aim for anti-angiogenic therapies in cancer treatment?
Why?
If there is too much anti- angiogenesis
- formation of resistance
- damage of healthy vasculature
- no adequate delivery of chemotherapy/drugs to cancer cells
So aim for: anti-angiogenic therapy that normalises vasculature
- reduces hypoxia
- Increase efficacy of conventional therapies
What is vascular mimicry?
It is the ability of a cancer to form vessesl-like channels in cancer cells (not via signaling of body cells)
–> agressive and poor prognosis!
