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Canc > Cancer 8: angiogenesis > Flashcards

Cancer 8: angiogenesis Flashcards

1
Q

Outline the diseases involving insufficient blood vessels

A

Baldness, MI, limb fracture, thrombosis

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2
Q

Outline disease inolvign vascular malformation

A

Angiodysplasia-HHT/VWD,

Cerebal malforamation- AVM (arteriovenous malformation)/CCM (cerebral cavernous)

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3
Q

Outline disease involving excessive blood vessel formation

A

Retinal disease, cancer, atherosclerosis and obesity

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4
Q

Outline the hree types of blood vessel formation

A

Vasculogenesis – bone marrow progenitor cell (during development). It involves progenitors that form a blood vessel from scratch).

  • Angiogenesis – sprouting (this is the most common in adults and involved in disease processes). Vessels sprout from a PRE-EXISTING blood vessel.
  • Arteriogenesis – collateral growth. May bypass blockage.
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5
Q

What initates angiogenesis

A

Hypoxia… turns quiescent endothelial cells to active state. Stimualtes a tip cell. The tip cells then influences neighbouring cells to become stalk cells.

Ultimately, the tip cell must engage with another tip cell

Cytoskeleton must change polarity

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6
Q

Outline key mediators of angiogenesis

A

Factors that inhibit and activators…. a balance

Inhib: thombospondin-1 and the statins

Activators: VEGFs

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7
Q

What occurs in endothelial cells that have been activated by growth factors, which were released due to hypoxia

A

The endothelial cells undergo a conformational change

  • They go from being part of a very organised monolayer, to sending out filopodia
  • Endothelial cells begin to migrate towards the growth factors
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8
Q

T/F tip cells themselves divide F

A

F… the tip cells do not divide… the neighbouting stalk cells divide behind them to push tip cels towards the GF
Tip will then meet another tip cell and fuse and stabilise

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9
Q

What growth factor controls gene expression in angioensis

A

HIF

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10
Q

How is the key angiogenic growth factor usually kept

A

Usually held bu von hippel-lindau tumor, a tumour supressor gene. pVHL ubiquinates and degrades HIF in the proteasome

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11
Q

What leads to expression of VEGF

A

When there is hypoxia: Von Hippel-Lindau does NOT bind to HIF so HIF is mobilised and it can translocate into the nucleus and drive the expression of genes involved in angiogenesis

  • One of the targets of HIF is the expression of VEGF (vascular endothelial growth factor)

Other targets of HIF are PDGF-b and TGF-a

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12
Q

How many members of the VEGF pathway

A

There are 5 members of the VEGF family: VEGF-A, VEGF-B, VEGF-C, VEGF-D, PIGF (placental GF

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13
Q

How many tyrosine kinase receptors for VEGF

and co refceptors

A

There are 3 tyrosine kinase receptors for VEGF: VEGFR-1, VEGFR-2, VEGFR-3

Coreceptors Neuropilin 1&2

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14
Q

What is the function of VEGF

A

VEGFR-2 is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival, proliferation.

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15
Q

T/F VEGFRs work in isolation

A

F: they can bind to each other and this can affect signalling and work with coreceptors neuropilin

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16
Q

Outline how the tip cell is selected

A

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

(you need to loosen the cells from the matrix using MMPs and loosen cell cell contacts at the VE-cadherin)

Then the notch signalling between adjactent endothelial cells at the angiogenic front

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17
Q

What is the point of the notch pathway

A

It is important to stop all the cells from becoming tip cells in response to VEGF concentration gradeints

So the notch signalling

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18
Q

Outline the notch pathway

A
  • Binding of a notch ligand, called DII4, (which is expressed in the tip cell) to the notch receptor (epxressed on the stalk cell) activates it by cleaving the intracellular domain (NICD)
  • NICD translocates to the nucleus in the stalk cell where it binds to the TF RBP-J and regulates transcription
  • It tells them that ‘I am the tip cell, you are the stalk cells’
  • The stalk cells then begin to divide and push the tip cell towards the growth factor
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19
Q

What is the relationship between VEGF and the noth signalling

A
  1. In stable blood vessels, Dll4 and Notch signalling maintain quiescence.
  2. VEGF activation increases expression of Dll4 (which cell is activated is still a mystery… related to VEGF concentration gradients)
  3. Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell.
  4. Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype.
  5. Adjacent cells (Stalk cells) form the base of the emerging sprout, and proliferate to support sprout elongation.
20
Q

What is important in stalk elongation and guidance of the tip

A
  1. VEGF guides the elongating sprout
  2. Marchophages carve out tunnels in the ECM and are involved in fusion of tips
  3. Pericytes involved in stabilisation
  4. Myeloid cells
21
Q

Outline pericyte function

A

Bind to the outside of the new sprout and send stabilising signals,

22
Q

What is the importance of VE cadherin

A

Constitutively expressed at junctions

Mediates adhesion between endothelial cells in the newly formed vessel

Controls contact inhibition of cell growth (ensure monolayer)

Promotes survival of EC

Look at Peter Clark’s lecture (lack of cadherin-mediated adhesion leads to binding of b-catenin to LEF1, which translocates to the nucleus to induce proliferation

23
Q

What is the importance of pericytes in blood vessel formation

A

Pericytes are important in the stabilisation of new blood vessels.. they are MURAL CELLS

THEY PRODUCE ANGIOPOIETIN 1….. A STABILISING AGENT

24
Q

Outline the actions of Ang-1 and Ang-2

When might Ang-2 increase

A

Ang-1 and Ang-2 are antagonistic ligands of the Tie2 receptor

  • Angiopoietin 1, when it binds to Tie2, promotes quiescence and stability in the vasculature + iunhiubits inflammatory gene expression (needed following the formation of the new blood vessel, as you need to convert the cell back to a stable state)
  • Ang-2 antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis (i.e. if you needed to form new vessel)

Ang-2 increasing in:

  • Congestive HF
  • Sepsis
  • CKD
25
Q

When must a tumour have new blood vessels

A

Tumours less than 1 mm3 receive oxygen and nutrients by diffusion from host vasculature

When tumours grow larger than this, they require new vessel networks

26
Q

How does the tumour

acquire new blood vessels

A

Larger tumors require new vessel network. Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels.

Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

(NOT CONSISTENT, DEPENDS ON WHICH ANGIOGENIC FACTOR TUMOUR CELL PRODUCES)

27
Q

What is the angiogenic switch

A

The angiogenic switch is 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

The point that a tumour becomes dependent on a new set of vasculature to grow

28
Q

Why are the vessels to tumours not like normal vssels

A

These are NOT properly formed because the signals are not physiological

  • There is an imbalance in the signals that are regulating angiogenesis
  • So in tumours, HAEMORRHAGE is common
29
Q

Characterise the tumour blood vessels

A

o Irregularly shaped, dilated, tortuous

o Not organised into definitive venules, arterioles and capillaries

o Leaky and haemorrhagic, partly due to the over-production of VEGF

o Perivascular cells often become loosely associated

o Some endothelial cells may recruit endothelial progenitor cells from the bone marrow

30
Q

How can VEGF be targeted in cancer therapy

A

Block the VEGF receptor or the subsequent signalling

31
Q

Name the antibody agains the VEGF ligand and how it works

A

Avastin (bevacizumab)

No VEGF signalling means that there is reduced proligerationg, migration etc of vessels

32
Q

T/F avastin has had a huge impact on cancer treatment, conferring increased quality of lfie

A

no overall survival advantage over chemo alone

no quality-of-life or survival advantage

33
Q

Outline the avastin side effects

A 
GI perforation
Hypertension
Proteinuria
Venous thrombosis
Haemorrage
Wound healing complications

(they occur because VEGF is essential for life, not just development and cancer)

34
Q

Is antioangiogenic therapy effectie?

A

In some cases benefits are transitory, and followed by a restoration of tumour growth and progression
In other cases there is no objective benefit

35
Q

Why might anti-angiogenic therapy not work

A

Two modes of unconventional resistance:

evasive resistance, an adaptation to circumvent the specific angiogenic blockade

intrinsic or pre-existing indifference (i.e. were not VEFG dependent)

This refers to general resistance to Abs

36
Q

Outline the possible mechanisms of resistance to anti-angiogenic therapy

A

LOSS OF RESPONSE CAN BE DUE TO:

reduced blood supply and reduced access by chemotherapeutic drugs

evasive resistance: other angiogenic growth factors take over : resistance to VEGF-based therapies

37
Q

What is vasculogenic mimicry

A

plasticity of aggressive cancer cells forming de novo vascular networks and is associated with the malignant phenotype and poor clinical outcome

38
Q

What is a problem with reducing angiogenesis in tumours for treatment

A

It also reduces the flow of chemotherpay drugs if there is reduced blood supply!

39
Q

Outline possible future of anti-angiogenic therapy

A

Anti-angiogenic therapy in combination with other anti-cancer therapies

Resistance: combinatorial strategies involving angiogenesis inhibition & drugs targeting resistance mechanisms

Novel non-VEGF targets – novel molecular mechanism

40
Q

Why is it so difficult to find better therapeutic strategies to inhibit cancer angiogensis

A

Tumours are complex three-dimensional (3D) structures with unique microenvironments

In vitro studies are performed on cell lines growing as two-dimensional (2D) monolayers, which do not mimic the complex interplay between tumor cells and their extracellular environment

Crucially, tumors receive nutrients and therapeutics through the vasculature, which is not included in in vitro 2D tumor models.

The phenotype of tumor cells when cultured in 2D (non vascularised) vs 3D models is different - drug screens in 2D models may be misleading

41
Q

How can angiogenic therapy be used in other diseases

A

Anti-angiogenic therapies for abnormal retina vascularization (diabetic retinopathy, wet AMD)

Pro-angiogenic therapies for ischemic diseases (myocardial infarction, peripheral ischemic disease)

42
Q

What is age related macular degeneration

A

Abnormal growth of choroidal blood vessels
“Leaky” vessels cause oedema
Visual impairment

43
Q

How is avastin used in AMD

A

Avastin used to block new blood vessels

44
Q

Give examples of physiological angiogenesis

A

Embryonic development
Menstrual cycle
Wound healing

45
Q

When could promotoign angiogenesis be useful

A

Therapeutic Angiogenesis for Coronary Artery Disease and Peripheral Artery Disease

Promote neovascularisation to prevent iscaemic damage

Canc (16 decks)

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