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Year 2 - MCD Cancer > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

When can physiological angiogenesis occur?

A
  • Embryonic development
  • Menstrual cycle
  • Wound healing
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2
Q

When can pathological angiogenesis occur?

A

• CANCER

  • Chronic inflammatory diseases
  • Retinopathies
  • Ischaemic diseases
  • Vascular malformations
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3
Q

What 3 things can angiogenesis be?

A

Insufficient
• e.g. baldness, MI

Involved in vascular malformations
• e.g. Angiodysplasia (HHT & VWD)

Excessive
• e.g. retinal disease, cancers, atherosclerosis

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4
Q

Angiogenesis is just one form of creating new blood vessels - what are some other ways?

A

VASCULOGENSIS
• using bone marrow progenitor cells

ARTERIOGENSIS
• collateral growth of vessels to accommodate occulusions

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5
Q

Basic model of sprouting angiogenesis?

A
  1. Selection of sprouting ECs
  2. Sprout outgrowth & guidance
  3. Sprout fusion & lumen formation
  4. Perfusion & maturation
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6
Q

What is a common trigger for angiogensis and explain what molecules help

A

Hypoxia

HIF
• Hypoxia-Inducible TF
• controls gene regulation

pVHL
• protein Van Hippel-Lindau TSG
• controls levels of HIF

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7
Q

Using the molecules invovled, describe angiogensis and hypoxia

A

Absence of O2
•pVHL does NOT bind to HIF
• HIF translocates to the nucleus –> binds to HIF-region
• induces translation of hypoxic factors

Presence of O2
• pVHL adds a hydroxyproline group to HIF
• HIF is therefore DEGRADED by a proteasome

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8
Q

VEGF and hypoxia?

A

One of the targets of HIF is VEGF (vascular endothelial GF)

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9
Q

Describe VEGF

A

5 families
• VEGF-A/B/C/D & Placental GF (PIGF)

3 TK-receptors
• VEGFR-1/2/3
AND
• co-receptors neuropilin (Nrp1, Nrp2)

VEGFRs can dimerise with other forms of VEGFRs
• i.e. VEGFR-2 –> VEGFR-3

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10
Q

Which VEGR is the major mediator of VEGF-dependant angiogenesis?

A

VEGFR-2

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11
Q

3 broad steps of the Angiogenetic Process?

A

(1) Tip Cells & Canonical Notch Signalling
(2) Sprout Outgrowth & Guidance
(3) Stabilisation & Quiescence

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12
Q

What happens in the 1st part of the Angiogentic Process (1) Tip Cells & Canonical Notch Signalling

A

Tip cells:
• Endothelial tip cells lead the outgrowth of blood-vessels towards gradients of VEGF
• Tip cell selection is based on “Notch Signalling” between the adjacent endothelial cells at the angiogenic front

Canonical Notch Signalling:
• Tip cells express NOTCH LIGANDS = binds to notch receptors on cells = signals division
• The intracellular domain of Notch (NICD) translocates to the nucleus and binds to the transcription factor RBP-J

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13
Q

Explain how Tip Cells are Selected for

A

Selection of Tip Cells:

  1. Stable – DII4 and Notch signalling maintain quiescence.
  2. Unstable – VEGF activation increases expression of DII4.
  3. DII4 drives Notch signalling in the adjacent cell which inhibits expression of VEGFR-2 (as they are stalk cells!).
  4. DII4-expressing Tip cells acquire a motile, invasive and sprouting phenotype.
  5. Stalk cells (adjacent cells) form the base of the sprout and proliferate to support the sprout elongation.
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14
Q

What happens in the 1st part of the Angiogentic Process (2) Sprout Outgrowth & Elongation

A

 MYELOID CELLS are recruited to support and guide the sprout (stimulated by Ang-II)

 Macrophages have a large role in angiogenesis anastomosis:
• Macrophages carve out tunnels in the ECM for subsequent capillary infiltration.
• Tissue-resident macrophages associate with the tip-cells during anastomosis to support the structure.

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15
Q

What is therefore the role of macrophages in the 2nd stage?

A

Stabilisers of new vessels

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16
Q

Explain what happens in the 3rd stage (3) Stabilisation & Quiescence

A

 Barrier formation facilitates the stabilisation of the vessel - it is associated with:

• VE-Cadherins & Ang-I

 Too much VEGF and there is too much sprouting and not enough stabilisation.

17
Q

Broadly state what stabilisation involves

A

(1) Switching OFF angiogenesis
• too much VEGF not ideal!

(2) Endothelium reformation
(3) Recruiting neural cells (pericytes)

18
Q

Explain (2) Endothelium Reformation

A

In order to form a monolayer (for the barrier), need to forn JUNCTIONS between cells

 VE-Cadherins:
• constitutively expressed at junctions
• controls contact inhibition of cell growth.
• promotes the survival of the ECs.

19
Q

Explain (3) Recruiting Neural Cells (pericytes)

A

Pericyte maturation facilitates the stabilisation of the vessel
• Mural cells = VSMCs and pericytes

 Pericytes and mural cells use an Ang/Tie-2 system to stabilise the vessel.

20
Q

Explain the Ang/Tie-2 system used by Pericytes & Mural cells to stabilise the cells

A

Angiopoietin-Tie 2 Lignad-Receptor System:

Ang-1 and Ang-2 ANTAGONISE the Tie-2 receptor:
 Tie-2 is a receptor that can bind Ang-1
 Ang-1 promotes vessel stability and inhibits inflammatory gene expression

 Ang-2 antagonises Ang-1 signalling
• leads to vascular instability and VEGF-dependant angiogenesis.
• Ang-2 levels are increased in sepsis, CKD and congestive heart failure.

SO Ang-1 = GOOD
Ang-2 = BAD

21
Q

What does the size of the tumour mean for its growth:
<1mm?
>1mm?

A

<1mm:
• receive oxygen and nutrients by diffusion from the host

> 1mm:
• require the “Angiogenic switch” so that the tumour can continue to grow
• this is done once the tumour starts to secrete angiogenic factors
• the “switch” occurs discretely AND at different steps in the tumour-progression pathway

22
Q

What are the characteristics of the Tumour Blood Vessels?

A

 Irregular shape
• Dilated, torturous

 Not organised into arteries/veins/capillaries

 Leaky (overproduction of VEGF)

 Perivascular cells loosely associated.

 May recruit endothelial progenitor
cells from bone marrow.

23
Q

Therapeutic strategies targeting the VEGF Pathway?

A

 Anti-VEGF Abs
• Avastin/Bevacizumab

 Soluble VEGF Receptors
• VEGF-Trap

 Anti-VEGFR Abs
• IMC-1121b

 Small-molecule VEGFR Inhibitors
• Vatalanib, Sunitinib

24
Q

Explain how Avastin/Bevacizumab are used?

A

ANTI-angiogenics
• via. Anti-VEGF Abs

 Used in combination with other drugs to treat cancer:
• Cervical, colorectal, glioblastoma, NSCLC, ovarian

 Avastin therapy has many side effects and a limited efficacy:
• This is as VEGF is not only essential for angiogenesis BUT also for HOMEOSTASIS OF ENDOTHELIUM

SEs:
 • GI perforation
 • hypertension
 • proteinuria
 • VTE
 • haemorrhage
 • wound healing complications

• No quality of life or survival advantage over chemo alone.

25
Q

Some anti-angiogenic therapies sometimes facilitate effects that seem PRO-TUMOUR GROWTH - explain this

A

o Sustained anti-angiogenic therapy can lead to too much ISCHAEMIA
• and thus release of hypoxic factors that further induce angiogenesis

o Vasculature may become refractory to treatment

o Vasculature may be inadequate for further delivery of drugs/oxygen.

26
Q

Some cancers are resistant to anti-VEGF therapies - explain how?

A

4 main modes of resistance to VEGF therapy:

(1) VEGF inhibition aggrevates hypoxia = increases tumour production of OTHER angiogenic factors OR tumour invasiveness
(2) Tumour vessels may be LESS SENSITIVE to VEGF inhibition due to vessel lining by tumour cells
(3) Tumour cells that recruit PERICYTES may be less responsive to VEGF therapy

(4) Tumour cell vasculogenic mimicry (VM) – the tumour cells remodel/organise themselves to resemble vessels which then once perfused by a single vessel allow adequate nutrient delivery to the whole tumour
• anti-angiogenic therapy will NOT affect this VM

27
Q

Explain Anti-Angiogenic Therapy for AMD

A

AMD - Age-related Macular Degeneration

 Abnormal growth of choroidal blood vessels = leaky vessels causing oedema = visual impairment

Avastin can be used as off-license to combat AMD

28
Q

The Future for the development of Anti-Angiogenic Drugs?

A

Problem:
– tumours are complex 3D structures that function in association with host vasculature
– so is difficult to mimic on a 2D-cell line monolayer when creating anti-angiogenic drugs

 “Tumour-on-a-chip” platform:
o Small system that incorporates human cells on a 3D ECM supported by perfused human micro-vessels.

29
Q

Potential for pro-angiogenics as therapies in cancer treatment?

A

For ischaemic diseases

– e.g. MI, peripheral ischaemia

Year 2 - MCD Cancer (14 decks)

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