Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

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

Lecture 15: Tumour Angiogenesis Flashcards

1
Q

What diseases is too much angiogenesis related too?

A

Cancer
Diabetic blindness
Age related macular degeneration
Arthiritis
Psoriasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What diseases is not enough angiogenesis related too?

A

Coronary artery disease
Stroke
Chronic wounds
Ageing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What s vasculogenesis?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Where does angiogenesis occur naturally in adults?

A

Uterine lining
Wound healing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is tumour angiogenesis?

A

When bloodvessels penetrate a small localised tumour allowing it to spread

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What prompts the release of angiogenesis factors?

A

High O2 = low HIF

Low O2 = high HIF = VEGF secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are different receptors relevant to angiogenesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions