Tumour vasculature Flashcards
What’s the difference between tumour and normal cell environment?
Tumour- has few pericyte(unstable), has a lot of fibroblasts(chemokine and cytokines so macrophages and inflammatory cells) and collagen(stiffer structure), inadequate blood flow, disorganized blood vessels(hypoxia), little lymph vessels(wastes in adequately removed)
Capillaries are made up of smooth muscle cells
False
What helps with the movement of blood in capillaries if they dont have smooth muscle cells?
endothelial cells and pericytes
What are the 3 kinds of capillary structures? WHta type of cancer is associated with each?
fenstered(brain, renal cell carcinomas), non fenestered(differentiated tumours), discontinuos(non differentiated tumours)
What are the two ways vessels can form?
- vasculogenesis
2. angiogenesis
Why does tumour associated angiogenesis resemble a wound that can’t heal?
Because it would recruit platlet factors and macrophages, increase inflammation and recruit other immune cell types that will feed the cycle and remodel the cells and vessels and the cycle never ends but keeps feeding itself.
Tumour is a physiological response that is initiated but never ends.
Which vessels do cancer cells intravsate into first?
post capillary venules
What are two abnormal classes of blood vessels only seen in tumours?
Capillary sprouts, blood channels without endothelial linings
What does the lymph node take from blood vessels?
Macromolecules, fluids, immune cells, lipids, pathogens
What processes does VEGF activate and which pathways?
proliferation, migation, capillary formation. MAPK and PI3K
What other pathways are involved in angiogenesis other than VEGF
DLL4, notch signalling
What’s the role of macrophages in tumour growth?
Mitogenetic activity, remodels and reorganizes the stromal cells leading to angiogenesis.
Immune evasion
What are the ways to target TAMS
We can inhibit their recruitment, direct killing, or prevent their M2 phenotype(protumour) and induce m1 ohenotype(antitumour)
What are the different VEGF’s and their functions
VEGFB- angiogenesis, closely related to VEGF
PLGF-more related to pathological conditions
VEGFC-more lymphiogenesis, induced by cytokine inflammation not by hypoxia
VEGFD-unknown
VEGF E-stimulates endothelial mitogenesis and permeability
What are some factors that activate and inhibt angiogenesis?
Activate: tgf-b, tnf-a
Inhibit:thrombospostin, endostatin
What is a way to monitor angiogenesis in vivo? What are the advantages and disadvantages?
intravital microscopy
Advantage-can monitor tumour in place
disadvantage-tumour can be abnormal in a confined place
What does delievery to the tumour depend on?
lymphatic network, blood flow, diffusion, vascular permeability
Blood flow math model?
q=pressure difference/zn or q=delta pressure/FR
Why does blood flow decrease with increasing tumour size? Id this consistent?
Because of structural abnormalities and necrosis. No this is varies even within the same tumour, can depend on functional state
Is blood flow different between primary tumours and carcinomas? Sarcomas and carcinoma
No and no
What does tissue oxygenation depend on?
arteriol o2 and nutritive o2
diffusion gradient
and shape of o2 dssoication curve
What does arterial o2 depend on?
shape of o2 dissociation curve
partial pressure of o2
haemaglobin concentration
temperature of blood
What is the trend seen with tissue oxygenation and tumour? How about if there is high blood flow rate
It’s usually hypoxic or anoxic and this varies in distribution in the same tumour, this is especially true in large tumours.
Then usually same oxygenation as normal tissues
What is the normal oxygen level found in tissues and what is the level that is categorized as hypoxic?
24-66mmhg
<20mmhg
How about pH and tumour trends? Consequences?
low pH, less glycolysis and more mitochondrial activity, less DNA synthesis, proliferation
What are Physiological barriers to drug delivery?
Resistance, AV shunting, high permeability hydrodynamic laws(low pressure gradient, high interstitial pressure but low vascular pressure)
What is meant by normalization window?
The perfect dosage that prunes weak and damaged vessels but strengthen the remaining ones so they can be targeted against through radiotherapy and this can only be done when the balance between pro and anti-angiogenic factors is restored
What are the two types of VDA’s? What is the difference?
VDA’s: biologics and small molecule agents
small molecule agent they target differences tumour and normal endotheliam cells
Biologics use antibodies and peptides that deliever toxins, pro-coagulants, pro-apoptotic effectors to the endothelial cells
What are two examples of small molecule VDA? Problems with it?
flavonoid
tubulin depolymerizing agent
very toxic
