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carcinogenesis Flashcards

angiogenesis: explain the basic mechanisms regulating angiogenesis, summarise the molecular mechanisms involved, explain the role of angiogenesis in health and disease, summarise the prospects for anti-angiogenic and pro-angiogenic therapies in cancer treatment (74 cards)

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1
Q

define angiogenesis

A

new blood vessel growth

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2
Q

3 physiological examples of angiogenesis

A

embryonic development, wound healing, menstrual cycle (uterine lining)

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3
Q

4 occurances when insufficient angiogenesis

A

baldness, MI (ischaemia), limb fractures, thrombosis

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4
Q

vascular malformations: 2 examples of angiodysplasia

A

hereditary haemorrhagic telangiectasia (HHT), Von Willebrand’s disease (VWD)

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5
Q

2 examples of cerebral malformations

A

arteriovenous malformation (AVM), cerebral cavernous malformation (CCM)

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6
Q

4 occurances when excessive angiogenesis

A

retinal disease, cancers, atherosclerosis, obesity

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7
Q

3 ways of new blood vessel formation

A

vasculogenesis (bone marrow progenitor cell), angiogenesis (sprouting in different angiogenic microenvironments), arteriogenesis (collateral growth)

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8
Q

stages of angiogenesis

A

EC receptor binding -> EC activation -> EC proliferation -> directional migration -> ECM remodelling -> tube formation -> loop formation -> vascular stabilisation

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9
Q

model of sprouting angiogenesis

A

selection of sprouting ECs -> sprout outgrowth and guidance -> sprout fusion and lumen formation -> perfusion and maturation

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10
Q

5 sprouting angiogenesis stages

A

tip/stalk cell selection -> tip cell navigation and stalk cell proliferation -> branching coordination -> stalk elongation, tip cell fusion, lumen formation -> perfusion and vessel maturation

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11
Q

angiogenesis balance: examples of inhibitors of angiogenesis

A

ECM, soluble factors or cell surface receptors; thrombospondin-1, statins

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12
Q

angiogenesis balance: examples of activators of angiogenesis (some essential, some required for modulation)

A

growth factors, soluble factors or cell surface receptors; VEGF (essential), FGF, PDGFB, EGF, LPA

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13
Q

angiogenesis balance: examples of things required for maturation and integrity of blood vessels

A

VE-cadherin, platelets, pathways (tissue or stimulus specific pathways)

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14
Q

what is a trigger for angiogenesis

A

hypoxia

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15
Q

what is HIF

A

hypoxia-inducible transcription factor, which controls regulation of gene expression by oxygen

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16
Q

what controls levels of HIF

A

pVHL (Von Hipper-Lindau) tumour suppressor gene

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17
Q

in absence of oxygen, what genes are coded for

A

pVHL doesn’t bind to HIF-a, so hypoxia-inducible genes are coded for, including VEGF

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18
Q

in presence of oxygen, what happens to HIF-a

A

pVHL binds to HIF-a, resulting in a proteasome destroying HIF-a

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19
Q

what does VEGF stand for

A

vascular endothelial growth factor

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20
Q

5 members of VEGF family

A

VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF)

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21
Q

3 tyrosine kinase receptors of VEGF

A

VEGFR-1, VEGFR-2, VEGFR-3, and co-receptors neuropilin (Nrp1 and Nrp2)

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22
Q

what VEGFR is the major mediator of VEGF-dependent angiogenesis

A

VEGFR-2

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23
Q

how does VEGFR-2 mediate angiogenesis

A

activates signalling pathway that regulates endothelial cell migration, survival and proliferation, so is essential

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24
Q

2 sections of VEGFR

A

dimerisation/binding domain, tyrosine kinase domain

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25
in sprouting angiogenesis, what leads the outgrowth of blood-vessel sprouts
specialised endothelial tip cells
26
where do specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards
gradients of VEGF
27
what is tip cell selection based on
Notch signalling between adjacent endothelial cells at angiogenic front
28
what are Notch receptors and ligands
membrane-bound proteins that associate through their EC domains
29
what does the IC domain of Notch (NICD) do after Notch ligand binding
translocates to nucleus and binds to transcription factor RBP-J
30
what maintains quiescence in stable blood vessels
DII4 and Notch signalling
31
pathway by which tip cells are selected by VEGF/Notch signalling
VEGF activation increases expression of DII4 -> DII4 drives Notch signalling, which inhibits expression of VEGFR2 in adjacent cell -> DII4-expressing tip cells acquire a motile, invasive and sprouting phenotype -> adjacent cells (stalk cells) form base of emerging sprout, and proliferate to support sprout elongation
32
what proteins assist in migration (tip cell guidance and adhesion)
integrins
33
what cells are recruited for sprout outgrowth and guidance
myeloid cell recruitment
34
role of macrophages in vessel anastomosis
carve out tunnels in ECM, providing avenues for capillary infiltration (tissue-resident macrophages can be associated with angiogenic tip cells during anastomosis)
35
role of platelets in phyiological angiogenesis
vascular development and lymphangiogenesis, wound healing
36
what forms a barrier to ensure stabilisation and quiescence
VE-cadherin and Ang-1 (angiopoietin-1), pericyte maturation
37
where is VE-cadherin constitutively expressed
at junctions
38
3 things that VE-cadherin does
homophilic interactions mediate adhesion between endothelial cells, controls contact inhibition of cell growth, promotes survival of EC
39
what cells help stabilise neovessels by producing stabilising factor angiopoietin-1
mural cells (pericyte cells)
40
location of pericytes
go around blood vessels
41
location of Tie2 receptor
almost exclusive to endothelial cells
42
what are antagonistic ligands of Tie2 receptor, and where are they released from
Ang-1 (pericyte), Ang-2 (endothelial cell)
43
what 2 things does Ang-1 do upon Tie2 receptor binding
promotes vessel stability and inhibits inflammatory gene expression
44
what 3 things does Ang-2 do upon Tie2 receptor binding
antagonises Ang-1 signalling, promoting vascular instability and VEGF-dependent angiogenesis
45
when are Ang-2 plasma levels raised
during disease, including congestive heart failure, sepsis and chronic kidney disease
46
VEGF pathway vs angiopoetin-Tie2 pathway
VEGF pathway essential for driving angiogenesis, angiopoetin-Tie2 pathway required for modulation
47
what do small tumours (<1mm3) receieve oxygen and nutrients by
diffusion from host vasculature (no need for angiogenesis)
48
what do large tumours require to receive oxygen and nutrients
new vessel network, facilitating progressive growth
49
how do large tumours gain a new vessel network
secretes angiogenic factors (e.g. VEGF, angiopoietins), driven by hypoxia, that stimulate migration, proliferation and neovessel formation by endothelial cells in adjacent established vessels
50
what is the angiogenic switch and when can it occur
discrete step in tumour development when tumour requires angiogenesis; can occur at different stages in the tumour-progression pathway, depending on tumour nature and microenvironment
51
describe tumour blood vessel shape
irregularly shaped, dilated, tortous
52
describe tumour blood vessel organisation
not organised into definitive venules, arterioles and capillaries
53
why are tumour blood vessels leaky and haemorrhagic
excessive VEGF so platelet activation releasing pro-angiogenic factors, as well as angiostatic molecules
54
what cells are often loosely associated with tumour blood vessels
pericytes cells
55
what might some tumours recruit from the bone marrow for tumour blood vessels
endothelial progenitor cells
56
what do cancer-associated fibroblasts (CAFs) secrete
ECM containing pro-angiogenic growth factors (VEGFA, FGF2 etc.)
57
why do tumour blood vessels have poor organisation
don't release all correct growth factors, pericytes are loosely associated (favouring leakage which is enhanced by angiopoietin 2), platelets release pro-angiogenic mediators (can be targeted)
58
2 agents which target VEGF
anti-VEGF antibodies, soluble VEGF receptors (e.g. VEGFR1)
59
agent which targets EC VEGFR
anti-VEGFR antibodies
60
agent which targets IC VEGFR
small-molecule VEGFR inhibitors
61
what is an anti-VEGF humanised MAb
avastin
62
side effects of avastin
GI perforation, hypertension, proteinuria, venous thrombosis, haemorrhgae, wound healing complications, limited efficacy as no overall quality of life or survival advantage vs chemotherapy alone (as no VEGF essential for normal endothelial cell angiogenesis)
63
3 modes of unconventional resistance by anti-angiogenic therapy in cancer
evasive resistance (adaption to circumvent specific angiogenic blockade), intrinsic or pre-existing indifference (vessel lining maybe less sensitive to VEGF inhibition), pericytes maybe less responsive to VEGF therapy
64
2 possible mechanisms of resistance to anti-angiogenic therapy
reduced blood supply and therefore reduces access by chemotherapeutic drugs, other angiogenic growth factors taking over
65
what is tumour cell vasculogenic mimicry (VM)
tumour cells "pretend" to be blood vessel cells; plasticity of aggressive cancer cells forming de novo vascular networks (malignant phenotype and poor clinical outcome)
66
problem of using sustained/aggressive anti-angiogenic therapy
may damage healthy vasculature leading to loss of vessels, creating vasculature resistant to further treatment and inadequate delivery of oxygen/drugs
67
how to do single cell RNASeq of tumour endothelium
tissue (tumour) -> isolate and sequence individual cells -> look at genes -> read counts -> compare gene expression profiles of single cells
68
purpose of single cell RNASeq
identify new molecular targets
69
4 challenges of finding better therapeutic strategies to inhibit angiogenesis in cancer due to in vitro research
tumours are complex 3D structures with unique microenvironments, in vitro studies grow as 2D monolayers (not 3D and with EC environment), tumours receive nutrients etc. through vasculature (not present in vitro), phenotype of tumour cells when cultured in 2D is different to 3D
70
function of a "tumour-on-a-chip" platform
development of a microphysiological system that incorporates human cells in a 3D extracellular matrix (ECM), supported by perfused human microvessels (reflect true tumour better), allowing better drug screening
71
when might anti-angiogenic therapies be used in other diseases
abnormal retina vascularisation (e.g. diabetic retinopathy, wet age-related macular degeneration)
72
when might pro-angiogenic therapies be used in other diseases
ischaemic diseases (e.g. MI, peripheral ischaemic disease)
73
what is age-related macular degeneration caused by, and symptom
abnormal growth of choroidal blood vessels, with leaky vessels causing oedema, and therefore causing visual impairment (main cause of blindness)
74
why is therapeutic angiogenesis used for coronary artery disease and peripheral artery disease
promotes neo-vascularisation to prevent ischaemic damage

Y2 MCD Cancer (20 decks)

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