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
