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Cancer Biology (BIO-6009A) > Lecture 15: Tumour Angiogenesis > Flashcards

Lecture 15: Tumour Angiogenesis Flashcards

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1
Q

What diseases is too much angiogenesis related too?

A

Cancer
Diabetic blindness
Age related macular degeneration
Arthiritis
Psoriasis

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2
Q

What diseases is not enough angiogenesis related too?

A

Coronary artery disease
Stroke
Chronic wounds
Ageing

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3
Q

What s vasculogenesis?

A

Process which creates the primary network of vascular endothelial cells that go on to become major blood vessels.

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4
Q

Where does angiogenesis occur naturally in adults?

A

Uterine lining
Wound healing

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5
Q

What is meant by the angiogenic switch?

A

Activators:
VEGF-A, VEGF-B / -C, FGF1, FGF2

Inhibitors:
Thrombospondin-1, -2, Interferon alpha/beta, angiostatin, endostatin, collagen 4 fragments, etc

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6
Q

What is tumour angiogenesis?

A

When bloodvessels penetrate a small localised tumour allowing it to spread

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7
Q

What is the Rip-Tag model of inslet tumour cell progression

A

Transgene: “V40 large an small T transcription driven by insulin promoter transcription in b-cells of islets of Lagerhans

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8
Q

What is the relevance of angiogenesis in ‘Intratumoural microvessel density’ (IMD)

A

IMD correlates with metastasis and survival

Correlations between IMD and VEGF, tumour growth, and metastasis

IMD - a good prognostic indicator in tumours that are particularly angiogenic (breast and prostate carcinoma)

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9
Q

What is the Chalkley Method?

A

Angiogenesis as a prognostic factor.

Grid containing 25 random dots is rotated so the max no. of points are on vessels of selected hot spot, overlying dots counted. Chalkley count = avrg no. of hits from 3 hot spots in the tumour

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10
Q

What is the process of angiogenesis

A
  1. Angiogenic factor release
  2. EC receptor binding
  3. EC activation
  4. EC proliferation
  5. Directional migration
  6. ECM remodelling
  7. Tube formation
  8. Loop formation
  9. Vascular stabilization
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11
Q

What prompts the release of angiogenesis factors?

A

High O2 = low HIF

Low O2 = high HIF = VEGF secretion

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12
Q

What is oxygen-dependent regulation of the HIF transcription factor?

A

Normoxia:
Degradation of HIF-1alpha via hydroxylation of proline residues in HIF1a subunits by prolyl hydroxyalse (PHD). VHL ind to elonginB and elonginC to form unbiquitin ligase complex.

Hypoxia:
Stabilization of HIF-1alpha = transcription of HIF inducible genes. proline hydroxylation does not occur, HIF1a & HIF1b forms heterodimer. HIFab binds to hypoxia response elements at promoter regions. Leads to VEGF expression.

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13
Q

What is Vib Hippel Lindau disease?

A

Caused by an inherited defect in VHL gene, HIG-1 constitutively activated = high lifetime risk of renal carcinoma.

VHL binds to HIF-1, targetting it for destruction

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14
Q

What is the structure of blood vessels?

A

Tunica intima = endothelial cells and basement membrane

Tunica media = supporting cells (smooth muscle/pericytes)

Tunica adventitia = supporting connective tissue

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15
Q

What are different receptors relevant to angiogenesis

A

VEGFR-1, -2, -3
TIE-1, -2
EphB-2, -3, -4
EphA-2

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16
Q

What is the angiopoietin family?

A

Four ligands: Ang-1, -2, -3, -4, which signal through the EC-specific receptor tyrosine kinases

Tie-1, and -2 are EC-specific

Ang-1 natural ligand for Tie-2

Ang-2, though to be an antagonist of Tie-2, by binding but not inducing phosphorylation of receptor in ECs

17
Q

What is meant by Tip Cell selection?

A

Tip Cell: induced by VEGF > high VEGFR2 signalling > low Notch signalling > extension of filopodia > highly motile > leads to new sprouts > guides migration

Stalk Cell: high notch signalling > low VEGFR signalling > Non-motile > Trails TC > maintains junctions > connects to parent

18
Q

What is DLL4

A

Delta-like-ligand-4. Expression induced by VEGF and acts to suppress capillary sprout formation by binding to and activating Notch receptor

19
Q

What is the role of proteases in angiogenesis

A

Activated ECs lining an existing vessel secrete proteases, which digest underlying BM and remodels ECM, ALLOWING capillary sprout in perivascular connective tissue

Plasminogen activator (PA)-plasmin system and matric metalloproteases (MMPs) described as having principle role here

20
Q

How can angiogenesis be studied in the lab?

A

In Vitro / ex vivo models
- EC tubulogenesis assays in matrigel, collagen, or fibrin
- Microfluidic flow models
- EC-pericyte co-cultures
- Aortic Ring 3D explant cultures

Developmental angiogenesis
- mouse embryonic hindbrain model
- Mouse retina model
- chorioalantoic membrane model
- Zebrafih
- Corneal pocket implant: rate/mouse/rabbit

Adult angiogenesis:
- placental angiogenesis
- wound angiogenesis
- matrigel plug assays
- tumour angiogenesis models: subcutaneous/spontaneous
- Hind-limb and coronary ischaemia models

21
Q

What is evidence for MMPs involvement in angiogenesis

A

MMP KO mice:
1. MMP-2-null mice
2. MMP-9-null mice
3. MT1-MMP-mull mice

22
Q

What is the important of integrins in angiogenesis?

A

Studies indicate alphaVbeta3 integrin is particularly important. Expressed on ECs undergoing angiogenesis, but not on resting endothelium.

anti-alphaVbeta3 Antibody, LM609, blocked bFGF-induced angiogenesis in CAM assay, but no effect on existing vessels

23
Q

What is the role of ephrins and Eph receptors?

A

Reciprocal signalling between two cell surface proteins.

Ephrins bind to Eph tyrosine kinases.

Bi-directional signalling: signalling via Ephrin-B and EphBR results in cytosolic domain of both the ligand and receptor being phosphorylated

24
Q

What is the importance in ephrins in vein/artery specification in development

A

Two types of EX in primary capillary plexus: (i) precursors arteries - ephrin B2 (ii) precursors of veins - EphB4

Replusion mediated by ephrins help segregate the two vessel types

Mice with ephrin B2 KO = vasculogenesis occurs but not angiogenesis

25
Q

What is the function of Eph and ephrins during vasculogenesis

A

Possible roles
1. Interaction between EphrinB2 and EphB4 at arterial-venous interface, may restrict intermingling of ECs or stimulate formation of new capillary sprouts by angiogenesis

  1. Co-expression of ligands and receptors by ECs might be req for contact-dependent communication via bi-directional signalling
  2. Eph/ephrin molecules expressed by adjacent mesenchymal cells ight be involved in patterning of vasculature
26
Q

What factors help regulate and maintain vascular remodelling

A
  1. VEGF
  2. Ang-1, -2
27
Q

What is anti-angiogenic therapy?

A

Targeting tumour vasculature is possible because the vessels are abnormal

28
Q

What are characteristics of tumour vessels?

A
  1. Leaky
  2. Only partially overlaid by pericytes and SMC
    3.
29
Q

What are angiogenic inhibitors?

A
  1. many are fragments of basement membrane proteins.
30
Q

What aren’t anti-angiogenic drugs working

A
  1. Side effects: bleeding, blood clots, hypertension, protein in urine, GI perforations and fistulas, birth defects
  2. Resistance to treatment
31
Q

Why could alphaVbeta3-integrin be a better target for anti-angiogenesis?

A
  1. Expressed in angiogenic bloodvessels, but not quinescent vessels
  2. Can regulate positively in tumour angiogenesis
32
Q

What is cilengitide?

A
  1. Blocks alphaVbeta3-integrin (& alphaVbeta5)
  2. RGD mimetic
  3. Unlike other anti-angiogenic drugs; well tolerated
33
Q

What is the aortic ring assay

A

Ex vivo assay for growth factor stimulated angiogenesis

34
Q

What happens to VEGF responsiveness in b3-null mice

A

Enhanced response. Increased VEGF-induced vessel infiltration in Matrigel implants in B3-null mice vs WT mice.

35
Q

Data shows that aVb3 integrin is not essential for tumour angiogenesis and raises hypothesis that it is a negative regulator

A
36
Q

What are other problems with anti-angiogenesis drugs?

A
  1. Dose choice
  2. Administration protocol
  3. Varied effects on varied tumours
  4. Established, slow-growing tumours have different angiogenic requirements
  5. Assessed by effect on tumour shrinkage
  6. tumours can ‘out-smart’ the therapy
  7. Tumours can be caught too late
37
Q

How can tumours escape anti-angiogenic therapy?

A
  1. Amplification of pro-angiogenic genes
  2. Escape via different modes of vascularization
  3. Secretion of multiple pro-angiogenic factors
  4. Recruitment of pro-angiogenic BMDCs
38
Q

What is metronomic therapy?

A

Targeting multiple angiogeneic pathways and using traditional cancer therapies

Cancer Biology (BIO-6009A) (24 decks)

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