Chapter 10 Flashcards
What is angiogenesis?
It is the process of forming new blood vessels from pre-existing ones by the growth of and migration of endothelial cells.
What is the process of forming new vessels from pre-existing ones?
Sprouting
When is angiogenesis normally seen? (3 things)
- embryogenesis
- Wound healing
- Female reproductive cycle
What is the diffusion limit of oxygen?
What does this mean?
100-200 micrometers
all cells must be within this range in order to receive the essential oxygen and nutrients
What typically happens to the cells within the core of the tumor?
They die of necrosis
To sprout from pre-existing vessels requires major reorganization.
What must occur?
- Destabilization of the current vessels
- Proliferation and migration of the endothelial cells
- Maturation
What regulates this?
The interaction between soluble mediators and their receptor.
Where do the mediators come from?
They are secreted by tumor cells and stromal cells.
True or false: the vasculature after new vessels formed during tumor growth is similar to vessels formed after wound healing.
False.
it will be leaky and tortuous
What is the angiogenic switch?
It is the balance between the inducers and inhibitors that activate or inactive angiogenesis.
How may angiogenesis be turned “on”?
- By increasing the activity of inducers
- Decreasing the activity of inhibitors
What are some of the anti-angiogenic factors we talked about?
- Angiostatin
- Endostatin
- Prolactin
- Protein 53
- Thrombospondin
What are some of the pro-angiogenic factors we talked about?
- VEGF
- fibroblast growth factor
- hepatocyte growth factor
- EGF
- PDGF
What are the non-specific growth factors that are important for angiogenesis?
- EGF
- FGF
- HGF
- PDGF
What are the vascular endothelium specific growth factors?
- VEGF - important for initiation of angiogenesis
- Angiopoietins (bind to Tie receptors) and are important for maturation
- Ephrins (bind to ephrin receptors) important for maturation as well
What are the five members of the VEGF family?
VEGF a, b, c, d,
and Placental Growth Factor
What are the three VEGF receptors?
What type of protein are they?
VEGF - 1, 2, 3
They are kinases
What interaction of VEGF and its receptor is responsible for the majority of angiogenesis?
VEGF A with VEGFR 2
What are the characteristics of VEGFR1?
it has weak affinity and kind of acts like a decoy.
What does VEGF C interact with and do?
It interacts with VEGFR 3 and contributes to the development of lymphatic vessels.
What secretes VEGF?
Tumor cells and the tumor-infiltrating immune cells do this
What releases sequestered VEGF in the ECM?
MMPs
What is VEGF important for? ( three things)
- endothelial cell proliferation
- Inducing permeability and leakage, by destabilizing the mature vessel allowing for sprouting
What are the VEGF responsive genes?
- EGF (epiregulin)
- MMPs
What else can the VEGF A signalling pathway induce?
It can induce the PI3K pathways
What does the PII3K pathway do for us?
- It inhibits apoptosis
- it increases the vascular permeability.
How do endogenous angiogenic inhibitors work?
They inhibit endothelial cells from migrating and proliferating
What does plasminogen become?
How does it become this?
What does the product function to do?
It is cleaved by MMPs to release angiotensin
Angiostatin acts to bind to endothelial cells to inhibit angiogenesis
How is endostatin made?
What does it do?
When there is proteolytic cleavage of collagen XVIII by MMPs
It blocks MAPK activation and MMP formation
what is concomitant resistance?
Some tumors produce anti-angiogenic factors, like angiostatin, that suppress the growth of distant metastases by inhibiting blood vessel formation. This keeps micrometastases in a dormant state while the primary tumor is present. After the primary tumor is removed, these inhibitory signals stop, allowing dormant metastases to grow.
How can surgery also induce angiogenic growth factors?
It damages tissue and induces wound healing which is also helpful for tumorigenesis
What is the angiogenic switch regulated by?
- Hypoxia
- Oncogenes and the loss of tumor suppressors.
What normally happens to HIF -1 alpha in normoxic conditions?
The HIF 1 alpha gets rapidly degraded by VHL protein, after it is hydrolyzed and then ubiquidated by VHL (Von Hipple Lindau)
What happens to HIF 1 alpha in hypoxic conditions?
It will not be degraded and can act as a coactivator to induce the expression of VEGF
How many different oncoproteins can induce angiogenesis?
How would they do this?
up to 30
Could be specific angiogenic factors like VEGF or general pathways like PDGF or EGF etc.
When there is abnormal production of growth factors by tumor cells it can be autocrine or paracrine.
What do these mean?
- Autocrine means that it would stimulate the proliferation of the same tumor cell
- Paracrine means that it would stimulate the growth of endothelial cells.
What do tumor suppressors do in the context of angiogenesis?
They have been shown to upregulate angiogenesis inhibitors.
For example, p 53 normally activates thrombospondin
What happens when angiogenesis is induced?
Endothelial cells extend filopodia and migrate toward the signal at the location of the highest VEGF A, activating the VEGFR 2
This signal is enhanced by neutropilin-1 (NRP-1) coreceptor and transduced via the MAPK cascade.
The result is that we see a formation of a tip cell at the forefront of the sprout.
Behind the tip cell are proliferating stalk cells that move along the VEGF gradient.
When the tip cells meet, they fuse and connect the lumen, allowing for blood flow in the new vessel.
What is vascular mimicry?
The process of tumor cells acting like endothelial cells to form vascular like structures
What is vasculogenesis?
Where do the progenitor cells come from?
When there is simply differentiation and proliferation of endothelial cells from endothelial progenitor cells.
They are called circulating endothelial progenitor cells or CEPs and they come from the bone marrow and are recruited by the tumor.
What do the drugs for anti angiogenic therapies do?
- Prevent cells from responding to pro-angiogenic signals
- Block the activity of the inducers
True or false: the drugs we use in anti angiogenic therapies are cytotoxic - they kill cells.
False
What are the advantages of of anti angiogenic drugs?
- They target endothelial cells that don’t mutate rapidly like tumor cells, so our treatment will keep working
- Normal angiogenesis doesn’t occur normally, so the effects are not going to be widespread
What is Bevacizumab?
When does it work the best?
It is a humanized monoclonal antibody against VEGF A
It works the best in the early stages of breast cancer, but VEGF A is crucial for angiogenesis in colon cancer so it works the best for that.
What was the result of endostatin as a therapy?
It was deemed non toxic but there was no clinical response that was observed.
Why might combination therapy be important for fully eliminating vasculature and tumors?
Because pericytes that surround the endothelium are partially resistant to VEGF-R inhibition and chemotherapy, but if PDGFR inhibitors are also given it may eliminate those pericytes and leave the raw endothelium which allows the first treatment to work.
What is vascular targeting?
How is this done?
Targeting selectively the tumor vasculature but not the normal blood vessels.
It is done by targeting:
- immature endothelium that relies on tubulin cytoskeleton for support, whereas the mature vasculature is supported by the basement membrane. This targeting is done by drugs that bind tubulin and disrupting the cytoskeleton.
What type of drug is Bortezomib?
It is a drug used to target vasculature and is a protease inhibitor.
