12 - Angiogenesis Flashcards
What is the “cut-off” size of a tumor where it will be able to receive efficient oxygen and nutrients by diffusion from host vasculature? What happens when the tumors outgrow this size?
1 cubic mm | bigger tumors = outgrow O2/nutrient supply = begin to starve and become hypoxic = need more »_space;> will secrete angiogenic factors
What are endothelial cells in relation to blood vessels?
cells that make up the vessel walls | these are the ones that divide and grow towards tumor to feed it
How do endothelial cells divide and grow?
in response to angiogenic factors and they must have the receptor in order to respond to it
What is the main angiogenic factor discussed?
VEGF
What are the 3 goals of endothelial cells during angiogenic events?
divide | migrate | survive
How do hypoxic tumor cells cope with hypoxia?
gaining more mutations = become genetically unstable
What is perfusion?
amount of fluid pushed through tissue | the more we have = the better (bc it is carrying O2 and nutrients)
What is HIF1-a? What is it’s function?
transcription factor | induces expression of VEGF and turns on genes with hypoxia response elements
What happens to HIF1-a in the presence of O2?
PHD hydrolates (OH) HIF1-a »_space;> VHL ubiquitin tags it for degradation
What is PHD?
proline hydroxylation = hydrolates proteins
What is VHL?
a ubiquitin ligase
What happens to HIF1-a in the absence of O2?
PHD proteins can’t put OH on HIF1-a bc no O2 present »_space;> HIF1-a goes into nucleus and turns genes on
On which promoters within the DNA will HIF1-a sit on?
hypoxia response elements (HRE)
What are the 4 types of genes that HIF1-a expresses in order to cope with hypoxia?
metabolism | vascular | iron/erythropoeisis | proliferation/survival | many others
In which cancer(s) are HIF1-a never or rarely expressed and why?
in melanoma because it’s skin and there is enough O2 on surface
What are 2 physiological characteristics (ie: hot, cold, basic, etc) are tumor cells?
hypoxic and acidic
What is ion trapping?
H+ ions trapped by chemotherapeutic drugs
Why would a chemotherapeutic drug that is basic will not work?
it will be neutralized in the acidic aggressive tumor cells = rendered ineffective
What is VEGF?
angiogenic growth factor | many isoforms (common one = VEGF-A) | dimer
What does expression of VEGF correlate within cancer patients? Why?
poor prognosis
What is the quality of the vessels tumor cells form? (4 things)
poor quality | leaky (dilated) | twisted | unstable = can easily fall apart without VEGF constantly present
What do the vessels that tumor cells make require in order to sustain its shape and not collapse?
constant stimulation of VEGF
If you are making VEGF, it is because you want to do what?
make more blood vessels
When would we make VEGF?
during growth development (childhood) | major injuries that destroy vessels
What cells replenish connective tissue?
fibroblasts
What cells replenish the epithelial cells?
adult stem cells
What does VEGF induce within the epithelial cell in order to move and migrate?
actin polymerization
In what 2 ways can vessels grow?
series or parallel
How do vessels growing in parallel affect perfusion?
less length = less friction = less resistance = more perfusion
How do vessels growing in series affect perfusion?
more length = more resistance = more pressure in vessels = increase chances of leaking = less perfusion
Tumors don’t have a uniform distribution of blood vessels, how does this affect drug treatments?
only well-vascularized tumor cells will get hit with the drug more than those that are less vascularized
If we do an anti-angiogenic drug, does it hurt the patient?
must analyze the perfusion to dictate if we are affecting anything | perfusion change = unaffected BUT affects the vasculature
Are there any natural occurring cells/proteins that inhibit angiogenesis?
family of proteins | tissue inhibitors - metalloproteases
What is TIMP3?
inhibits angiogenesis - happens in body naturally
What will happen if you throw in TIMP3 in a population expressing VEGF? What does this indicate?
decreases number of vessels shown | inhibitory affect is only specific to TIMP3
What is the correlation between VEGF and metastasis?
as tumor cells expressed VEGF = ability to metastasize became greater
What was the approach Avastin was aiming to take in inhibiting VEGF?
use of humanized murine antibodies to bind to VEGF = neutralize them
What is endostatin? How is it used as a chemotherapeutic drug?
binds to sugars and can bind to certain receptors | upon binding = freezes endothelial cells from dividing (reasons are unknown) = stops growth of blood vessels
What is the Chick Chorioallantoic Assay?
used to study angiogenesis in lieu of mouse models | use teflon ring on membrane in egg = add drug within area = observe presence or absence of vasculature
What is the benefit of using zebrafish to study the hematopoietic system?
they are transparent = can see the vasculature and what is going on inside
What is an adjuvant?
additional supportive drug
What is a regimen?
combination of drugs
What will happen to hypoxic tumor cells without an O2 supply?
will undergo necrosis and die
What is the tumor path as HIF1-a induces glycolysis cycle?
leads to acidosis »_space;> angiogenesis and progression
