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Year 2 Collin > Cancer 8 - Angiogenesis > Flashcards

Cancer 8 - Angiogenesis Flashcards

1
Q

Give 3 examples of physiological angiogenesis

A
  1. Embryonic development
  2. Wound healing
  3. Menstrual cycle
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2
Q

What can insufficient angiogenesis cause?

A

Baldness
Ischaemia/MI
Limb fractures
Thrombosis

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3
Q

What can vascular malformations (improper angiogenesis) cause

A

Angiodysplasia (HHT + VWD), cerebral malformations (AVM/CCM)

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4
Q

What can excessive angiogenesis cause?

A

Retinal disease, cancers, atherosclerosis, obesity

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5
Q

Name a pro-angiogensesis stimulus

A

VEGF - causes activated cell to change polarity + cytoskeleton which drives vessel sprouting —- forming TIP cell

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6
Q

What do adjacent cells to the tip cell do?

A

Divide to stabilise the new vessel

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7
Q

How is a balance of angiogenesis maintained

A

Balance between inhibitors and activators ensured

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8
Q

What are the triggers for angiogenesis

A

Hypoxia - mediated by

  1. HIF –> Hypoxia Inducible TF (controls regulation of gene expression by oxygen)
  2. pVHL –> Von Hippel-Lindau TSG, controls HIF levels
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9
Q

Explain how pVHL interacts with HIF

A

If sufficient oxygen - pVHL binds HIF - causing ubiquitination in HIF –> HIF degraded

If insufficient oxygen –> pVHL doesn’t bind HIF –> more HIF enters nucleus and binds HIF-beta —> drives transcription of genes promoting angiogenesis

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10
Q

How many members are in the VEGF family

A

5

VEGF A/B/C/D
Placental Growth Factor (PIGF)

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11
Q

What type of receptors bind the VEGF family and how many are there?

What is the coreceptor?

A

3 tyrosine kinase receptors - different dimer combinations

Co receptor is neuropilin 1/2

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12
Q

Which is the major VEGFR that mediates VEGF-dependent angiogenesis

A

VEGFR2 - activates signal pathways that regulate endothelial cell migration, survival, proliferation

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13
Q

Endothelial tip cells lead outgrowth of blood-vessel sprouts towards what gradient?

A

VEGF gradient

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14
Q

How is it determined which endothelial cell becomes the tip cell?

A

Notch signalling

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15
Q

How does a notch receptor and ligand bind

A

Notch receptor (stalk cell) and ligand (delta-ligand-4 on tip cell) are both membrane bound proteins —> they associate via extracellular domains

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16
Q

What happens when the notch ligand binds the receptor

A

Intracellular domain (NICD) gets cleaved and translocates to the nucleus –> binds to TF RBP-J

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17
Q

Explain how VEGF/notch signalling helps select the tip cells

A
  1. DII4 and notch signalling stable in quiescent cells –> because signalling on both cells
  2. VEGF activation - increased DII4 expression
  3. Cell with more DII4 expression becomes the tip - DII4 expression drives notch signalling - inhibiting VEGFR2 expression in adjacent cell
  4. The DII4 expressing tip cells acquire motile, invasive, sprouting phenotype
  5. Adjacent cells form base of emerging sprout and proliferate to support sprout elongation
18
Q

Which 2 things are involved in sprout outgrowth?

A
  1. Cytoskeletal reorganisation

2. Myeloid cell recruitment (e.g. in retina can help process)

19
Q

What is the role of VE-cadherin in sprouting angiogenesis

A
  1. Constitutively expressed at junctions
  2. Mediates adhesion between endothelial cells
  3. Controls contact inhibition of cell growth
  4. Promotes survival of endothelial cell
20
Q

What type of cancer can arise from loss of cadherin control

A

Epithelial cancers

21
Q

How do mural cells (e.g. pericytes) help stabilise me-vessels?

A

Pericytes normally wrap around capillaries - also produce Angiopoietin-1 (stabilising factor)

22
Q

Ang1 and Ang2 both bind to the Tie2 receptor. Explain their antagonistic effects

A

Ang1/Tie2 = vessel stability + anti-inflammatory gene expression

Ang2/Tie2 = antagonises Ang1 signalling, promotes vascular instability and VEGF dependent angiogenesis

23
Q

Which Ang is released more in inflammation as it helps the inflammatory response?

A

Ang2

24
Q

Plasma Ang2 is raised in disease. Name some diseases in which it is higher

A
  1. Congestive heart failure
  2. Sepsis
  3. CKD
25
Q

What is Vascular Permeabiltiy Factor?

A

Same as VEGF

26
Q

What is avastin?

A

Anti-VEGF monoclonal antibody - used for advanced colorectal cancer but turned out to be ineffective

27
Q

Small tumours (<1 mm3) survive from oxygen and nutrients received how?

A

Via diffusion from host vasculature

28
Q

How do larger tumours survive?

A

They secrete angiogenic factors - creates a new vessel network that stimulates migration, proliferation + be-vessel formation by endothelial cels (in existing adjacent cells)

29
Q

What is the angiogenic switch

A

The point in the growth of a tumour where it now depends on angiogenesis for growth

30
Q

5 features of tumour blood vessels

A
  1. Loss of balance of angiogenesis factors
  2. Irregularly shaped, dilated, tortuous and fragile —> meaning rupture-prone
  3. Not organised well into venues, arterioles, capillaries
  4. Leaky + haemorrhage (due to excessive VEGF)
31
Q

Give an example of an anti-VEGF humanised monoclonal antibody

A

Avastin (bevacizumab)

typically used in advanced stages of cancer

32
Q

What is Avastin used for in first line treatment of metastatic colorectal carcinoma?

A

Avastin + 5-fluorouracil

33
Q

What are the side effects of using Avastin in cancer therapy?

No overall survival advantage over chemo alone

A 
GI perforation
Hypertension
Proteinuria
Venous thrombosis
Haemorrhage
Wound healing complications
34
Q

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

A
  1. Evasive resistance = adaptation to circumvent specific angiogenic blockade
  2. Intrinsic/pre-existing indifference = if tumour more dependent on different GFs
35
Q

Give 6 cancers that bevacizumab (Avastin) may be used to treat

A
  1. Cervical
  2. Colorectal
  3. Glioblastoma
  4. Non-small cell lung cancer
  5. Ovarian epithelial, Fallopian tube / primary peritoneal cancer
  6. Renal cell cancer
36
Q

What are 2 ways to feed a tumour?

A
  1. Angiogenesis - tumour secrete factors which stimulates vessel growth –> vessel grows into tumour
  2. Tumour cell vasculogenic/vascular mimicry –> plasticity of aggressive cancer cells forming de novo vascular networks –> associated with malignant phenotype and poor prognosis
37
Q

What is the solution to the 2D in vitro tumour modelling problem currently being faced?

A

“Tumour on a chip” - in vitro disease model with vasculature also

38
Q

Give an example of antiangiogenic therapy in other diseases?

A

Abnormal retina vascularisation (e.g. diabetic retinopathy/ wet AMD)

39
Q

What causes age related macular degeneration

A

Abnormal growth of choroidal blood vessels —> leaky vessels cause oedema causing visual impairment

40
Q

What is the main cause of blindness?

A

AMD

41
Q

How can therapeutic angiogenesis be used for coronary artery disease and PAD

A

Promote neovascularisation - to prevent ischaemic damage

e.g. induce neo-angiogenesis in ischaemic myocardium using human GFs (may require proteins, stem cells, gene therapy)

Year 2 Collin (114 decks)

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