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Y2 MCD Cancer > carcinogenesis > Flashcards

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

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
Q

in sprouting angiogenesis, what leads the outgrowth of blood-vessel sprouts

A

specialised endothelial tip cells

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26
Q

where do specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards

A

gradients of VEGF

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27
Q

what is tip cell selection based on

A

Notch signalling between adjacent endothelial cells at angiogenic front

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28
Q

what are Notch receptors and ligands

A

membrane-bound proteins that associate through their EC domains

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29
Q

what does the IC domain of Notch (NICD) do after Notch ligand binding

A

translocates to nucleus and binds to transcription factor RBP-J

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30
Q

what maintains quiescence in stable blood vessels

A

DII4 and Notch signalling

31
Q

pathway by which tip cells are selected by VEGF/Notch signalling

A

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
Q

what proteins assist in migration (tip cell guidance and adhesion)

A

integrins

33
Q

what cells are recruited for sprout outgrowth and guidance

A

myeloid cell recruitment

34
Q

role of macrophages in vessel anastomosis

A

carve out tunnels in ECM, providing avenues for capillary infiltration (tissue-resident macrophages can be associated with angiogenic tip cells during anastomosis)

35
Q

role of platelets in phyiological angiogenesis

A

vascular development and lymphangiogenesis, wound healing

36
Q

what forms a barrier to ensure stabilisation and quiescence

A

VE-cadherin and Ang-1 (angiopoietin-1), pericyte maturation

37
Q

where is VE-cadherin constitutively expressed

A

at junctions

38
Q

3 things that VE-cadherin does

A

homophilic interactions mediate adhesion between endothelial cells, controls contact inhibition of cell growth, promotes survival of EC

39
Q

what cells help stabilise neovessels by producing stabilising factor angiopoietin-1

A

mural cells (pericyte cells)

40
Q

location of pericytes

A

go around blood vessels

41
Q

location of Tie2 receptor

A

almost exclusive to endothelial cells

42
Q

what are antagonistic ligands of Tie2 receptor, and where are they released from

A

Ang-1 (pericyte), Ang-2 (endothelial cell)

43
Q

what 2 things does Ang-1 do upon Tie2 receptor binding

A

promotes vessel stability and inhibits inflammatory gene expression

44
Q

what 3 things does Ang-2 do upon Tie2 receptor binding

A

antagonises Ang-1 signalling, promoting vascular instability and VEGF-dependent angiogenesis

45
Q

when are Ang-2 plasma levels raised

A

during disease, including congestive heart failure, sepsis and chronic kidney disease

46
Q

VEGF pathway vs angiopoetin-Tie2 pathway

A

VEGF pathway essential for driving angiogenesis, angiopoetin-Tie2 pathway required for modulation

47
Q

what do small tumours (<1mm3) receieve oxygen and nutrients by

A

diffusion from host vasculature (no need for angiogenesis)

48
Q

what do large tumours require to receive oxygen and nutrients

A

new vessel network, facilitating progressive growth

49
Q

how do large tumours gain a new vessel network

A

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
Q

what is the angiogenic switch and when can it occur

A

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
Q

describe tumour blood vessel shape

A

irregularly shaped, dilated, tortous

52
Q

describe tumour blood vessel organisation

A

not organised into definitive venules, arterioles and capillaries

53
Q

why are tumour blood vessels leaky and haemorrhagic

A

excessive VEGF so platelet activation releasing pro-angiogenic factors, as well as angiostatic molecules

54
Q

what cells are often loosely associated with tumour blood vessels

A

pericytes cells

55
Q

what might some tumours recruit from the bone marrow for tumour blood vessels

A

endothelial progenitor cells

56
Q

what do cancer-associated fibroblasts (CAFs) secrete

A

ECM containing pro-angiogenic growth factors (VEGFA, FGF2 etc.)

57
Q

why do tumour blood vessels have poor organisation

A

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
Q

2 agents which target VEGF

A

anti-VEGF antibodies, soluble VEGF receptors (e.g. VEGFR1)

59
Q

agent which targets EC VEGFR

A

anti-VEGFR antibodies

60
Q

agent which targets IC VEGFR

A

small-molecule VEGFR inhibitors

61
Q

what is an anti-VEGF humanised MAb

A

avastin

62
Q

side effects of avastin

A

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
Q

3 modes of unconventional resistance by anti-angiogenic therapy in cancer

A

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
Q

2 possible mechanisms of resistance to anti-angiogenic therapy

A

reduced blood supply and therefore reduces access by chemotherapeutic drugs, other angiogenic growth factors taking over

65
Q

what is tumour cell vasculogenic mimicry (VM)

A

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
Q

problem of using sustained/aggressive anti-angiogenic therapy

A

may damage healthy vasculature leading to loss of vessels, creating vasculature resistant to further treatment and inadequate delivery of oxygen/drugs

67
Q

how to do single cell RNASeq of tumour endothelium

A

tissue (tumour) -> isolate and sequence individual cells -> look at genes -> read counts -> compare gene expression profiles of single cells

68
Q

purpose of single cell RNASeq

A

identify new molecular targets

69
Q

4 challenges of finding better therapeutic strategies to inhibit angiogenesis in cancer due to in vitro research

A

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
Q

function of a “tumour-on-a-chip” platform

A

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
Q

when might anti-angiogenic therapies be used in other diseases

A

abnormal retina vascularisation (e.g. diabetic retinopathy, wet age-related macular degeneration)

72
Q

when might pro-angiogenic therapies be used in other diseases

A

ischaemic diseases (e.g. MI, peripheral ischaemic disease)

73
Q

what is age-related macular degeneration caused by, and symptom

A

abnormal growth of choroidal blood vessels, with leaky vessels causing oedema, and therefore causing visual impairment (main cause of blindness)

74
Q

why is therapeutic angiogenesis used for coronary artery disease and peripheral artery disease

A

promotes neo-vascularisation to prevent ischaemic damage

Y2 MCD Cancer (20 decks)

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