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MCD: Cancer > Angiogenesis > Flashcards

Flashcards in Angiogenesis Deck (45)
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1
Q

What is angiogenesis?

A

New blood vessel growth.

2
Q

What physiological roles does angiogenesis have in health?

A

Embryonic development
Wound healing
Menstrual cycle

3
Q

What conditions are dependent on insufficient angiogenesis?

A

Baldness
MI- ischaemia
Limb fractures
Thrombosis

4
Q

What conditions are dependent on vascular malformations?

A

Angiodysplasia
HHT and VWD
Cerebral malformations
AVM/CCM

5
Q

What conditions are dependent on excessive angiogenesis?

A

Retinal disease
Cancers
Atherosclerosis
Obesity

6
Q

What are the 3 types of blood vessel formation?

A

Vasculogenesis (bone marrow progenitor cell)
Angiogenesis (sprouting)
Arteriogenesis (collateral growth)

7
Q

How is angiogenesis regulated?

A

Balance between inhibitors and activators.

8
Q

What are the inhibitors of angiogenesis?

A
Thrombospondin-1
Angiostatin
Endostatin
Canstatin
Tumstatin
9
Q

What are the activators of angiogenesis?

A
VEGFs
FGFs
PDGFB
EGF
LPA
10
Q

What is a key trigger of angiogenesis?

A

Hypoxia

11
Q

What is HIF?

A

Hypoxia-inducible transcription factor.

Controls regulation of gene expression by oxygen.

12
Q

What is pVHL?

A

Von Hippel-Lindau tumour suppressor gene.

Controls levels of HIF.

13
Q

What is VEGF?

A

Vascular endothelial growth factor.

Family of 5 members: VEGF-(A-D), placental growth factor (PlGF).

14
Q

What are the 3 tyrosine kinase receptors of VEGF?

A

VEGFR-(1-3)

15
Q

What is the major mediator of VEGF-dependent angiogenesis?

A

VEGFR-2

Activates signalling pathways that regulate endothelial cell migration, survival, proliferation.

16
Q

What is tip cell selection based on?

A

Notch signalling between adjacent endothelial cells at the angiogenic front.

17
Q

What are tip cells?

A

In sprouting angiogenesis, specialised endothelial tip cells lead the outgrowth of blood vessel sprouts towards gradients of VEGF.

18
Q

What are Notch receptors and ligands?

A

Membrane-bound proteins that associate through their extracellular domains.

19
Q

What does the intracellular domain of Notch (NICD) do in the canonical Notch signalling pathway?

A

Translocates to the nucleus and binds to the transcription factor RBP-J.

20
Q

What maintains quiescence in stable blood vessels?

A

DII4 and Notch signalling.

21
Q

What increases expression of DII4?

A

VEGF activation

22
Q

What dose DII4 drive?

A

Notch signalling

23
Q

What does Notch signalling inhibit?

A

Expression of VEGFR-2 in the adjacent cell

24
Q

In VEGF/Notch signalling, what are the qualities of the phenotype acquired by DII4-expressing tip cells?

A

DII4-expressing tip cells acquire a motile, invasive and sprouting phenotype.

25
Q

What is the role of stalk cells in VEGF/Notch signalling?

A

Adjacent cells (stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation.

26
Q

What are the roles of VE-cadherin in angiogenesis?

A

Constitutively expressed at junctions
Mediates adhesion between endothelial cells
Controls contact inhibition of cell growth
Promotes survival of EC

27
Q

What is the role of mural cells in angiogenesis?

A

Help to stabilise neovessels.

28
Q

What is the role of pericytes in angiogenesis?

A

Produce the stabilising factor, angiopoietin-1.

29
Q

What diseases are Ang-2 plasma levels raised in?

A

Congestive heart failure
Sepsis
Chronic kidney disease

30
Q

What does Ang-1 binding to Tie2 result in?

A

Promotion of vessel stability

Inhibition of inflammatory gene expression

31
Q

What are Ang-1 and Ang-2 in relation to Tie2?

A

Antagonistic ligands of the Tie2 receptor.

32
Q

What is the role of Ang-2 in angiogenesis?

A

Antagonises Ang-1 signalling

Promotes vascular instability and VEGF-dependent angiogenesis

33
Q

What is the angiogenic switch?

A

Discrete step in tumour development that can occur at different stages in the tumour progression pathway, depending on the nature of the tumour and its microenvironment.

34
Q

How do tumours smaller than 1mm^3 receive oxygen and nutrients?

A

Diffusion from host vasculature.

35
Q

What are the properties of tumour blood vessels?

A

Irregularly shaped, dilated, tortuous
Not organised into definitive venues, arterioles and capillaries
Leaky and haemorrhagic, partly due to excessive VEGF
Perivascular cells are often loosely associated
Some tumours may recruit endothelial progenitor cells from the bone marrow

36
Q

How do larger tumours (>1mm^3) receive oxygen and nutrients?

A

Require new vessel network.
Tumour secretes angiogenic factors that stimulate migration, proliferation, and neovlessel formation by endothelial cells in adjacent established vessels.
Newly vascularised tumour no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

37
Q

What are the side effects of Avastin?

A
GI perforation
Hypertension
Proteinuria
Venous thrombosis
Haemorrhage
Wound healing complications
38
Q

What was the first anti-angiogenic clinically proven to extend survival in cancer?

A

Anti-VEGF humanised mAb, Avastin.

39
Q

What is the efficacy of Avastin therapy for cancer?

A

Limited efficacy.
No overall survival advantage over chemotherapy alone.
No quality of life or survival advantage.

40
Q

What are the 2 modes of unconventional resistance to anti-angiogenic therapy in cancer?

A

Evasive resistance- an adaptation to circumvent the specific angiogenic blockade.
Intrinsic or pre-existing indifference.

41
Q

What is vasculogenic mimicry?

A

Cancer cells form blood-carrying channels to supplement traditional angiogenesis in supplying nutrients to tumours.
Plasticity of aggressive cancer cells forming de novo vascular networks.
Associated with malignant phenotype and poor clinical outcome.

42
Q

What is age-related macular degeneration (AMD)?

A

Abnormal growth of choroidal blood vessels
‘Leaky’ vessels cause oedema
Visual impairment

43
Q

What can anti-angiogenic therapies be used for (other than cancer)?

A

Abnormal retina vascularisation (diabetic retinopathy, wet AMD).

44
Q

What can pro-angiogenic therapies be used for?

A

Ischaemic disease (myocardial infarction, peripheral ischaemic disease)- promote neovascularisation to prevent ischaemic damage.

45
Q

What is the ‘tumour-on-a-chip’ platform?

A

Microphysiological system that incorporates human cells in a 3D ECM, supported by perfused human micro vessels.
In vitro disease models incorporating tumour cells and vasculature may improve tumour modelling and drug screening.