Tumour vasculature

Question 1

What’s the difference between tumour and normal cell environment?

Answer 1

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)

Question 2

Capillaries are made up of smooth muscle cells

Answer 2

False

Question 3

What helps with the movement of blood in capillaries if they dont have smooth muscle cells?

Answer 3

endothelial cells and pericytes

Question 4

What are the 3 kinds of capillary structures? WHta type of cancer is associated with each?

Answer 4

fenstered(brain, renal cell carcinomas), non fenestered(differentiated tumours), discontinuos(non differentiated tumours)

Question 5

What are the two ways vessels can form?

Answer 5

1. vasculogenesis

2. angiogenesis

Question 6

Why does tumour associated angiogenesis resemble a wound that can’t heal?

Answer 6

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.

Question 7

Which vessels do cancer cells intravsate into first?

Answer 7

post capillary venules

Question 8

What are two abnormal classes of blood vessels only seen in tumours?

Answer 8

Capillary sprouts, blood channels without endothelial linings

Question 9

What does the lymph node take from blood vessels?

Answer 9

Macromolecules, fluids, immune cells, lipids, pathogens

Question 10

What processes does VEGF activate and which pathways?

Answer 10

proliferation, migation, capillary formation. MAPK and PI3K

Question 11

What other pathways are involved in angiogenesis other than VEGF

Answer 11

DLL4, notch signalling

Question 12

What’s the role of macrophages in tumour growth?

Answer 12

Mitogenetic activity, remodels and reorganizes the stromal cells leading to angiogenesis.
Immune evasion

Question 13

What are the ways to target TAMS

Answer 13

We can inhibit their recruitment, direct killing, or prevent their M2 phenotype(protumour) and induce m1 ohenotype(antitumour)

Question 14

What are the different VEGF’s and their functions

Answer 14

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

Question 15

What are some factors that activate and inhibt angiogenesis?

Answer 15

Activate: tgf-b, tnf-a
Inhibit:thrombospostin, endostatin

Question 16

What is a way to monitor angiogenesis in vivo? What are the advantages and disadvantages?

Answer 16

intravital microscopy
Advantage-can monitor tumour in place
disadvantage-tumour can be abnormal in a confined place

Question 17

What does delievery to the tumour depend on?

Answer 17

lymphatic network, blood flow, diffusion, vascular permeability

Question 18

Blood flow math model?

Answer 18

q=pressure difference/zn or q=delta pressure/FR

Question 19

Why does blood flow decrease with increasing tumour size? Id this consistent?

Answer 19

Because of structural abnormalities and necrosis. No this is varies even within the same tumour, can depend on functional state

Question 20

Is blood flow different between primary tumours and carcinomas? Sarcomas and carcinoma

Answer 20

No and no

Question 21

What does tissue oxygenation depend on?

Answer 21

arteriol o2 and nutritive o2
diffusion gradient
and shape of o2 dssoication curve

Question 22

What does arterial o2 depend on?

Answer 22

shape of o2 dissociation curve
partial pressure of o2
haemaglobin concentration
temperature of blood

Question 23

What is the trend seen with tissue oxygenation and tumour? How about if there is high blood flow rate

Answer 23

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

Question 24

What is the normal oxygen level found in tissues and what is the level that is categorized as hypoxic?

Answer 24

24-66mmhg

<20mmhg

Question 25

How about pH and tumour trends? Consequences?

Answer 25

low pH, less glycolysis and more mitochondrial activity, less DNA synthesis, proliferation

Question 26

What are Physiological barriers to drug delivery?

Answer 26

Resistance, AV shunting, high permeability
hydrodynamic laws(low pressure gradient, high interstitial pressure but low vascular pressure)

Question 27

What is meant by normalization window?

Answer 27

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

Question 28

What are the two types of VDA’s? What is the difference?

Answer 28

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

Question 29

What are two examples of small molecule VDA? Problems with it?

Answer 29

flavonoid
tubulin depolymerizing agent
very toxic