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1

what makes 99.9% of cancers fatal and what is this process facilitated by?

metastasis is facilitated by angiogenesis

2

what can be done medically to metastatic tumours?

very little

3

what is angiogenesis and why is it required?

the formation of new blood vessels
- it is essential for normal tissue and tumours to have good supply of oxygen and nutrients so that biosynthesis can occur

4

what happens as you move away from the capillary?

oxygen availability decreases very rapidly (it follows an inverse square law)

5

how does the blood supply in a tumour look different from that of healthy tissue?

it is disorganised and random as a pose to ordered and regular

6

why do tumours induce vascularisation of their environment?

so it can get good access to oxygen and nutrients

7

what does good vasculature allow in terms of tumour growth?

allows tumour to grow to large sizes

8

if we artificially induce angiogenesis in a microtumour, what is observed? what is then observed if this is then removed?

the tumour can expand
when the vasculature is removed the tumour regresses due to apoptosis and necrosis and you end up with a tumour similar in size to the initial microtumour that was limited in size

9

what might being able to control the vasculature of a tumour allows?

being able to control the size of the tumour and stop tumour cells getting access to factors that they need in order to proliferate

10

in addition to oxygen and nutrients, what does angiogenesis also provide?

an escape route for cells to migrate from

11

when oxygen is limited in a tissue, what occurs?

cells release factors which stimulate capillaries to sprout towards them, this is a normal physiological process

12

new vasculature allows the tumour to expand, what then occurs?

expansion means there are now new areas of low oxygen, this stimulates the production of further vasculature

13

where is Epo secreted?

from the kidneys

14

describe the appearance of Epo and what does it do?

its helical bundle which binds receptors on the surface of cells in BM and promotes red blood cell production

15

people that train and live at altitude are likely to have increased Epo production, why is this?

so that they produce more red blood cells to provide oxygen to their tissue

16

what happened with Epo in relation to the Tour de France?

some people had injected Epo to increase oxygen carrying capacity of the blood
it was hard to detect as injected proteins are similar to endogenous proteins

17

what does HIF stand for? and what is it?

Hypoxia Inducible factor
it is a heterodimeric transcription factor
HIF-1α and HIF-2α or HIF-3α and HIF-1β

18

what is hypoxia?

a deficiency in the amount of oxygen reaching the tissues

19

what is HIF sensitive to? and what does it do?

hypoxia
HIF is active at low levels of oxygen and switches on a cascade that allows angiogenesis to take place

20

what target sequences does HIF bind? and give an example of a gene that has one of these in their promoter

HRE target sequence
Epo

21

how is HIF regulated?

in normoxia, HIF is rapidly degraded
in hypoxia, HIF is stabilised

22

give two example experimental example that show that HIF degradation is reliant on Ubiquitin-mediated proteasomal degradation?

- proteasome inhibition stabilises HIF
- mutations in E1 stabilise HIF

23

what is the cancer prone disease that is characterised by highly vascularised tumours in the retina, brain and spinal chord called? and what gene has been seen to be upregulated in this disease?

Von Hippel-Lindau Syndrome
some components of HIF are upregulated

24

a second gene is associated with Von Hippel-Lindau Syndrome, what is it and how is it mutated in this syndrome?

VHL
disease mutations arise in the beta domain which disrupts normal interacts with HIF

25

VHL is an important regulator of HIF, which domain bind HIF and which domain regulates HIF?

beta domain bind HIF while the alpha domain regulates HIF

26

what is seen when the alpha domain is truncated from VHL?

VHL still binds HIF but does not regulate HIF in any way

27

which protein does the alpha domain show homology to? and what does this suggest?

skp2
this suggests that the alpha domain might mediate recruitment of ubiquitination machinery and cause HIF destruction

28

there is a second protein protein interaction motif in the alpha domain, name three proteins that interact with this,

eloB, EloC and cullin2

29

what are elongins?

there are big proteins that mediate other protein protein interactions

30

which domain of VHL does HIF bind?

beta domain