angiogenesis

Question 1

hypoxia

Answer 1

low oxygen on tissue

Question 2

what do cancers need to grow?

Answer 2

oxygen, glucose, amino acids, vascular system

Question 3

what is a pericyte?

Answer 3

support cell for small vessels

Question 4

what is the stroma made of

Answer 4

fibroblasts and other cell types

Question 5

what happens at the cell cell junctions of endothelial cells?

Answer 5

there is increased permeability so cells can leave the blood as well as fluids and solutes

Question 6

what does it mean when you say oxygen has a diffusive limit

Answer 6

it cannot diffuse forever

Question 7

how close are cells to a blood vessel in the venous end

Answer 7

10µm because the blood is deoxygenated so we need a short diffusion distance

Question 8

how close are cells to a blood vessel in the arterial end

Answer 8

70µm because the blood is oxygenated

Question 9

how do cancers stay oxygenated (6)

Answer 9

1. induce vasodilation
2. sprouting angiogenesis
3. intussusceptive angiogenesis
4. anaerobic metabolism
5. vascular co-option
6. vasculogenesis

Question 10

what is intussusceptive angiogenesis

Answer 10

splitting existing blood vessels

Question 11

what is vascular co-option?

Answer 11

when cancers grow along blood vessels

Question 12

what is vasculogenesis

Answer 12

developing new vessels de novo (spontaneously)

Question 13

what does VEGF stand for

Answer 13

vascular endothelial growth factor

Question 14

what does VEGF do

Answer 14

makes vascular endothelial cells grow

Question 15

VEGF-A structure

Answer 15

glycosylated protein, 121-189 amino acids long

Question 16

summary of the process of angiogenesis

Answer 16

VEGF production and secretion, endothelial activation - binds to a receptor and induces Ca2+ uptake in the cell and other cellular pathways. Increase in permeability, matrix degradation, this allows pericyte withdrawal, new blood vessel spout forms and endothelial migration occurs, cell division behind migrating sprout, lumen formation, sprout connection and blood flow

Question 17

what

Answer 17

It also activates standard map kinase ras signalling

Question 18

what happens to the O2 in the cell as it proliferates

Answer 18

the amount of it is reduced

Question 19

what does the reduction of O2 in the cell activate

Answer 19

Transcription factor HIF1 (hypoxia inducible factor)

Question 20

what happens when HIF1 is activated

Answer 20

translocated to nucleus and turns on and off any genes, including VEGF, VEGF is produced and secreted, it activates VEGFR (VEGF receptor) which activates endothelial cells

Question 21

what are the different isoforms of HIF1

Answer 21

HIF1-α and HIF1-β

Question 22

what happens to HIF1-α in normal conditions

Answer 22

it is rapidly degraded by oxygen

Question 23

what happens to HIF1-α in hypoxic conditions

Answer 23

it binds to HIF1-β to form a
transcription factor complex which has slowed degradation

Question 24

what is the hypoxia response element

Answer 24

region of DNA with a particular sequence that the HIF complex can recognise

Question 25

what happens when the HIF complex comes across the hypoxia response element

Answer 25

it binds to the sequence and then further transcription factors can bind and form a big complex which can go along and make mRNA for protein production

Question 26

what TF binds after the HIF complex binds

Answer 26

TBP (Tata binding protein)

Question 27

what does TBP do

Answer 27

finds the polymerase II

Question 28

what happens when TBP and polymerase II bind

Answer 28

they can turn genes on and off

Question 29

what happens to glucose transporters in hypoxia

Answer 29

they can be turned on and off so that the cell can overload itself with glucose so it can respire by glycolysis

Question 30

how are the effects of VEGF reduced

Answer 30

with a VEGF antibody

Question 31

how does VEGF cause leakiness

Answer 31

1. blood flow (more blood more leak)
2. angiogenesis - growing more leaky blood vessels
3. increase vascular permeability (make specific vessels leaky)

Question 32

what does the VEGF mechanism depend on

Answer 32

Ca2+

Question 33

how does VEGF weaken vessel walls

Answer 33

it enhances proteinase activity

Question 34

what happens in pericyte withdrawal

Answer 34

the pericytes move away from the blood vessel, creating space for the endothelial cells to migrate

Question 35

intussusception (1st type of angiogenesis)

Answer 35

fibroblasts and pericytes push in on endothelial cell and so it becomes 2 separate vessels which move apart

Question 36

sprouting angiogenesis (2nd type)

Answer 36

endothelial cells put out filopodia towards sources of VEGF (tip cell)

Question 36

which cells divide in sprouting angiogenesis

Answer 36

the stalk cells (directly behind the tip cell)

Question 37

how does only one sprout occur and not many

Answer 37

tip cells repress the cells around them and stop them from being able to become tip cells

Question 37

what happens when 2 filopodia meet

Answer 37

they signal to the other cells that they have found another tip cell, the sprouts grow closer to each other and then the tip cells differentiate into endothelial cells to make a vascular loop

Question 38

what does angiopoietin 1 (ang1) do

Answer 38

stabilises vessels, opposite of VEGF

Question 39

what does angiopoietin 2 (ang2) do

Answer 39

destabilises vessels, blocks effects of ang1

Question 40

what does platelet derived growth factor do (PDGF)

Answer 40

recruits pericytes

Question 41

what is bevacizumab (Avastin)

Answer 41

a drug that binds to circulating VEGF

Question 42

what is Ramucirumab

Answer 42

an antibody that binds to the VEGF receptor, inhibiting its activation