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cancer - year 2 > angiogenesis > Flashcards

angiogenesis Flashcards

1
Q

where does angiogenesis occur

A

small bv - endothelium is not surrounded by lots of layers

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2
Q

summarise the cascade of events in angiogenesis *

A

startes becasue of hypoxia - triggers the release of angiogenic factors eg VEGF

VEGF binds to an extracellular receptor - causing intracellular signalling

this activates endothelial cells

extracellular actiation leads to BM degredation

leads to EC proliferation and directional margination

causes ECM remodelling, tube formation, loop formation (a-v differentiation)

vascular stabalisation

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3
Q

when does angiogenesis occur physiologically *

A

development in embryo - mediated by podoplanin and clec-2

menstrual cycle

wound healing - medialted by GF and cytokines

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4
Q

what pathology is angiogenesis involved in *

A

cancer

chronic inflammatory diseases

rheumatoid arthritis - mediated by RMPs

retinopathy - mediated by VEGF adn PDGF

ischemic diseases - bv grow at base of atherosclerotic plaque - mediated by p-selectin and vWF

vascular malformations

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5
Q

are all bv the same *

A

no - they have differnet angiogenic microenvironments

therefore angiogeneis is different in development to in wound healing

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6
Q

describe in vivo models of angiogenesis

A

in zebrafish blood vessels stained - can see the sprouting of new vessels

in mouse retina is vascularised after birth - we can stain for bv - green is a TF and is seen in every endothelial cells

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7
Q

describe the different types of vascular growth

A

vasculogenesis - in embryo - involves progenitors from the bone marrow

angiogenisis - sprouting - main form in adults

arteriogenesis - collateral growth when there is an occlusion

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8
Q

describe the regulators of angiogenesis *

A

large number of molecules can influence angiogenesis

VEGF is essentila

VWF - not essential but w/o it the vessel growth is not perfect

some molecules are pro- and anti-angiogenic depending in the microenvironment and the stage of the cascade, some molecules get cleaved

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9
Q

what are the inhibitors of angiogenesis *

A

Extracellular Matrix:

  • Thrombospondin-1
  • Angiostatin
  • Endostatin

Soluble factors:

  • sVEGF-R
  • IL-10
  • IL-12
  • TNF-a

Cell surface receptors:

•avb3

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10
Q

what are the activators of angiogenesis *

A

Growth factors:

  • VEGF family
  • FGF family
  • TGF b
  • PDGF

Soluble factors:

  • IL-6
  • Factor XIII
  • TNF-a

Cell surface receptors:

•avb3

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11
Q

why do we need molecules for maturation and stability of bv *

A

once we have made bv they are useful w/o stabalising them

need to be maintained because they are crucial for the function of tissues

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12
Q

factors that are involved in maturation and stability of bv *

A

VE-Cadherin (Junctions)

Angiopoietin/Tie2

Notch pathway

ERG pathway

Platelets

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13
Q

describe the mechanism of sprouting angiogenesis *

A

angiogenic factor stimulates endothelial activation

1 cell is hit be the factor - becomes the tip cell, surrounding cells become the stalk cells

the tip cell starts sprouting and stalk cells push them up

tip cell is involved in navigation and stalk cell in proliferation

the stalk cells elongate and tip cells fuse forming the lumen

then the vessel is perfused and matures

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14
Q

describe how hypoxia triggers apoptosis *

A

hypoxia-inducible TF controls regulation of gene expression by oxygen

Von Hippel–Lindau tumor suppressor gene, controls levels of HIF

in presence of oxygen - HIF-a binds to pVHL, pVHL takes HIF-a to protease so HIF-a is destroyed

in absence of oxygen ie hypoxia - pVHL leaves HIF-a - HIF-a binds to DNA dribing transcription of genes that promote angiogenesis eg VEGF

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15
Q

what is the family of VEGF *

A

Family of 5 members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF)

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16
Q

describe the VEGF receptors *

A

there are 3 TK receptors - VEGFR-1 VEGFR-2 and VEGFR-3

and co receptors neuropilin (Nrp1 and Nrp2) - have VEGF binding domains

the VEGF receptors can form dimers

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17
Q

what are the main VEGF(R) *

A

VEGFR-2 and VEGF-a are the main players of VEGF dependant angiogenesis, they activate signalling pathways that regulate endothelial cell preliferation, survival and migration

18
Q

describe stage 1 of angiogenesis *

A

astrocyte or macrophage produces VEGF

VEGF binds to VEGFR on endothelial cells - these cells become the tip cells which drive the formation of new bv and tells the cells next to it to become stalk cells

the tip cells lead the bv to gradients of VEGF

tip cell selection is controlled by the NOTCH signalling pathway between adjacent endothelial cells at the angiogenic front

19
Q

describe the canonical notch signalling pathway *

A

this pathway is essential for development and basic functioning

notch receptors and ligands are membrane bound proteins that associate through their extracellular domains

the ligand and receptors are on opposite cells

the ligand on the tip cell binds to the receptor on the stalk cell - the notch intracellular domain (NICD) of the receptor is cleaved and enters nucleus - binds to TF RBP-J - regulates proliferation and the behaviour of the cell

one of the big ligands is Dll4

20
Q

describe how the selection of tip cells relates to VEGF and notch *

A

in stable bv Dll4 and notch signalling maintain quinescence

VEGF increases activation of Dll4 expression

Dll4 drives notch signalling which inhibits VEGFR2 expression in adjacent cell

DII4 expressing tip cells acquire motile, invasive and sprouting phenotype

stalk cells form the base of the emerging sprout, and proliferate to support elongation

21
Q

describe stage 2 of angiogenesis - stalk elongation and tip guidance *

A

the tip cell migrates to the tissue

integrins are adhesion receptors and make the cells move and sense the ECM

myeloid cells are recruited - they support sprouting by carving a tunnel in matrix so endothelial cells dont have to work so hard - the macrophages wrap around the tip of the bv

platelets are full of regulators of angiogeneis - they release podoplanin, clec 2, GF and cytokines for physiological angiogenisis and p-selectin, vWF, PMPs, VEGF and PDGF for pathological angiogenesis

22
Q

describe stage 3 of angiogenesis - stabalisation and quinescence *

A

need to form juntions - they are homophilic interactions ie by the same proteins on opposite cells - the proteins are TM proteins - have extracellular bit that binds and intracelluler bit that controls signalling

at adheren junctions adhesion is promoted by cadherin

at tight juction adhesion is mediated by claudins, occludin, members of the JAM family and ESAM

these junctions control permability, allow inflammatory cells to enter, and control contact inhibition - allow endothelial cells to grow in a single layer

the junctions promote the survival of

23
Q

describe the role of pericytes *

A

they are mural cells - they help stabalise the neovessels

they dont cover the whole of the vasculature - they just wrap around

they produce molcules for stability ie angiopoitin

24
Q

describe the angiopoitin-tie 2 ligand receptor system *

A

Tie2 is an endothelial receptor - Ang-1 and ang-2 bind to it

ang-1 binds in homeostatic bv to stabalise junction and promote survival - inhibits inflammatory gene expression

when bv is activated because of inflammation or during angiogenesis - ang-2 is released from weibel-palade bodies, transcription is increased; ang-2 synergises with VEGF

ang-2 antagonises ang-1 signalling and promotes vascular instability and VEGF-dependant angiogenesis

ang-2 plasma levels are increased in congestive HF, sepsis and CKD - high levels of ang-2 is not a good thing because destabalising systemically

it modulates angiogenesis but is not essential for initiation

25
Q

describe angiogenesis in tumours *

A

tumors <1mm3 recieve oxygen and nutrients by diffusion from host vasculature

large tumours require a new vessel network

tumours secrete angiogenic factors eg VEGF driven by hypoxia that stimulate migration, proliferatioon and neovessel formation by endothelial cells in adjacent established vessels

tumours dont secrete all factors and stimulation of bv is not normal

newly vascularised tumour doesnt rely on diffusion from host vasculature, fascilitating progressive cell death

26
Q

what is teh angiogenic switch *

A

a discrete step in tumour development taht can occur in differnet stages in tumour progression pathway - depending on the tumour and its microenv

tumour goes through stafes - dormant - perivascular detachment and vessel dilation - onset of angiogenic sprouting - continuous sprouting (new vessel formation and maturation, recruitment of perivascular cells) - tumour vasculature

27
Q

describe tumour bv *

A

they are irregularly shaped, dilated and tortuous

not organised into definitive venules, arterioles and capillaries,

leaky and haemorrhagic - partly becasue of over production of VEGF

perivascular cells are loosely associated

some tumours may recruit endothelial progenorator cells from the marrow - controversial

there are occlusions

28
Q

describe the promotion of tumour angiogenesis *

A

it is a multi-cellular response

cancer associated fibroblasts secrete ECM and factors that modulate angiogenesis (VEGFA, FGF2, CXCL12, PDGFC) - doesnt give off all the factors involved physiologically

pericytes are loosely associated with tumour associated bv (TABV) - this favours chronic leakage - enhanced by ang-2

tumour has haemorrhage because bv are not functioning properly - attracts platelets - platelets release proangiogenic mediators and proteases that support the proliferation and activation of cancer associated fibroblasts - PDGFB and TGFbeta

29
Q

describe the role of platelets in tumour angiogenesis *

A

there is a link between cancer progression adn thrombocytosis

activated platelets are a source of pro-angiogenic factors - VEGFA, platelet derived GF (PDGFs), FGF2

also a source of angiostatic molecules - thromobospondin 1, plasmin activator inhibitor 1 (PAI1), endstatin

tumours cause plateley activation, aggregation and degranulation

disrupting platelets doesnt impair tumour angiogeneisis - but the overall action of platelets is pro-angiogenic

30
Q

describe therapeutic strategies to inhibit VEGF signalling *

A

anti-VEGF Ab - molecules block VEGFR and then downstream signalling

aflibercept blocks VEGFA and VEGFB adn PIGF

bevacizumab blocks VEGFA
ramucizumab blocks VEGFR-2

can get VEGFR kinase inhibitors

31
Q

evidence for VEGF inhibition by VEGFR1 (Flt-1)*

A

cells transfected with control or sFlt-1 plasmid to promote Flt-1 (VEGFR1 - soluble bit of receptor) expression

VEGFR1 binds to VEGF and mops it up - so VEGF cant bind to receptor on cells

Flt-1 acts in vivo to reduce tumour growth but not in vitro - indivating bv involvement

32
Q

what is avastin *

A

FDA approved

it is anti-VEGF monoclonal Ab

33
Q

describe avastin SE and limited efficacy *

A

no overall survival advantage over chemo alone

no QOL advantage

benefits are transient - followed by restoration of tumour growth and progression - tumour becomes resistant

SE are because VEGF is essential endo survival factor

SE:

  • GI perforation
  • Hypertension
  • Proteinuria
  • Venous thrombosis
  • Haemorrage
  • Wound healing complications
34
Q

potential mechanisms of SE for anti-VEGF therapy in cancer *

A

VEGF inhibition aggravates hypoxia increasing tumour;s production of other angiogenic factors/increases tumours invasiveness

tumour vessels may be less sensitive to VEGF inhibition due to vessel lining by tumour cells or endo cells derived from tumours

tumour cells that recruit pericytes may be less responsiev to VEGF therapy

tumour cell vasculogenic mimicry - also known as vascular mimicry - describes plasticity of aggressive cancer cells - forming de novo vasculature - tumour cells pretend to be bv and form channels, vessels hook up to channels within tumour mass, so doesnt matter if block vegf

35
Q

what are the anti-angiogenic strategies *

A

aim to normalise the vasculature

dont block all factors - otherwise make it hypoxic and also chemo will not be able to access the tumour

if you kept giving aggressive anti-angiogenic therapy - you would damage healthy vessels and create vasculature resistant to treatment and inadequate for delivering drugs and ox

36
Q

what is the future for 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
37
Q

describe the process of finding novekl treatment mechanisms*

A

single cell RNASeq of tumour endo

this allows you to study all genes transcribed in cell by studying RNA

gives you a profile of expressuion of individual cells in body

eg look at tumour and normal endothelial cells and can see that the endothelial cells are differnet - know what genes are expressed in tumour and not in normal endo - help you find new molecular targets

38
Q

describe anti-VEGF for age related macular degeneration

A

AMD is because of abnormal growth of choroidal bv - they are leaky vessels and cause oedema = visual impairment

avastin was used off label - lucentis was developed from avastin for treatment of AMD

High efficacy of both treatments in maintaining or improving vision

Many patients become refractory to treatment >2 years

39
Q

what is the challenge in finding therapeutic strategies to inhibit ang *

A

tumours are complex 3d structures with own micro-env - lack in-vitro models

studies are performed on cell lines as 2d monolayes that dont mimic interplay between tumour and env

phenotype of tumour in 2 an 3d is different

crucially vascualture is not involved in vitro

40
Q

describe tumour on a chip *

A

it is the development of new in vitro models for anti-angiogenic drug screens

model that is closer to the body microenv

have blood and all variety of cells

bv grow on microchip - put tumour cells on - show the growth of cells - use chemo and show that they work in this network

41
Q

why would you use pro-angiogenic drugs *

A

to alloow drug delivery to the tumour - the chemo drugs need to reach a certain concentration to be effective - they would not be effective with anti-angiogenesis drugs

cancer - year 2 (18 decks)

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