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Cancer, Autoimmunity and Transplant Immunology > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

what is an endothelium?

A
  • a major organ which comprises the blood vessels of the body
  • in direct contact with blood - non-thrombogenic surface, so blood will not clot when in contact with endothelium
  • thin membrane
  • largest mass in the body to perfuse tissues
  • most metabolically and genetically active cell in the body - expresses the most genes
  • master regulator of the body
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2
Q

what is angiogenesis?

A

the growth of new blood vessels from existing vessels

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3
Q

is angiogenesis highly active in adults?

A
  • low level of angiogenesis
  • in females, occurs during menstrual cycle, where uterus regrows lining and where ovary forms follicle and matures the egg - essential for reproduction
  • blocking angiogenesis can act as a contraceptive, as it inhibits egg development
  • doesn’t happen in men unless they are in wound healing or in the gut due to damage to intestinal lining
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4
Q

what is the structure of epithelial tissues?

A
  • Epithelial tissues are outside to separate from outside environment
  • can be one cell thick or multiple layers
  • Epithelium sits on basement membrane and continually proliferates to provide barrier function
  • basement membrane is what contacts the outer environment in all tissues e.g. the blood
  • beneath basement membrane is the stromal tissue which can grow blood vessel
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5
Q

how is cancer induced?

A

a mutation in a cell (either due to genetic or environmental factor)
- this mutation may lead to loss of control in cell growth
- cell proliferates uncontrollably to form localised tumour

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6
Q

how does a tumour effect the epithelial tissue structure?

A
  • loss of contact inhibition with basement membrane
  • layer organisation is lost
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7
Q

what is a benign tumour?

A
  • usually, people over the age of 60 have small, benign tumours found frequently throughout the body
  • these are lesions which are not damaging and do not metastasise, as they don’t grow large enough
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8
Q

what happens when a tumour grows too large?

A
  • As tumour proliferates, it gets bigger and becomes hypoxic (normoxia is 1-4% oxygen, hypoxia is below 1%) in the centre
  • Tumour can’t be fully perfused and uses up oxygen
  • this induces transcriptional changes in the cancer
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9
Q

how do large tumours respond to hypoxia?

A
  • hypoxia activates TFs which can cause release of angiogenic factors from the cancer cells
  • these diffuse beneath basement membrane and stimulate growth of new blood vessels from original vessels
  • endothelial cells form vessels which penetrate the tumour
  • Forms a vascularised tumour – first step needed for metastasis
  • Basement membrane is broken by the tumour – cancer can become malignant as it reaches the stroma
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10
Q

how can a benign and malignant tumour be distinguished?

A

benign = basement membrane in tact

malignant = basement membrane is broken
- cells can enter bloodstream and undergo metastasis

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11
Q

what TF is activated by hypoxia in tumours?

A

– hypoxia–inducible factor switches on 10% of genome, including glycolytic genes, downregulates Krebs cycle genes – switch from oxidative phosphorylation to glycolysis – angiogenic switch

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12
Q

what evidence is there that tumour growth is angiogenesis-dependent?

A

Inject cancer cells to anterior chamber of rabbit eye:
- Some cells would remain as single cells, suspended in the anterior chamber indefinitely
- But if the cancers attach to iris, which has a rich blood supply, they can promote blood vessel growth into eye to vascularise the tumour, leading to rapid tumour growth

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13
Q

what are pericytes?

A

these cells bind to the surface of stable, mature vessels and maintain them

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14
Q

how do angiogenic factors function?

A

Tumour produces VEGF, FGF
- the factors cause pericytes to be expelled from the vessel, meaning it is no longer stabilised
- with the vessel now exposed, the factors bind to their receptors on resting endothelial cells to polarise the endothelial cells
- there is release of proteases to degrade the ECM
- Endothelial cell begins proliferating and migrating towards tumour
- Basement membrane is broken down

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15
Q

how are the new vessels in tumours organised?

A

Healthy tissue has big vessels becoming capillaries that join up again
- Hierarchical structure

In tumour:
- Blood vessels are in a mess – lack of organisation – highly branched and abnormal
- Vessels in tumour are malformed as they have been hijacked and haven’t been through tight developmental process
- more vessels, but less functional

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16
Q

is blood flow efficient in a tumour?

A

Blood flow in tumours is very poor compared to healthy tissue
- tortuous, leaky, variable flow - no directionality, or no blood flow at all
- high intestitial fluid pressure

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17
Q

why are cytotoxic drugs limited in cancer treatment?

A

Cytotoxic cancer drugs fail because the drug can’t enter the tumour due to poor vascularisation

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18
Q

what are the consequences of the lack of blood flow in angiogenic tumours?

A

Cancer becomes hypoxic
- lack of blood flow, so lack of oxygen
- oxygen tension is from 0-1% (anoxic-hypoxic)

Cancer also becomes acidic
- lack of oxygen means OXPHOS cannot occur
- tumour can only use glycolysis for ATP, which releases lactic acid as waste = acidic TME

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19
Q

how do hypoxia and acidity effect cancer?

A
  • hypoxia induces expression of 2000 genes - large chunk of genome due
  • normally, TFs transcribe around 10-50 genes
  • hypoxic TFs are promiscuous and cause massive induction of gene expression
  • causes differential gene expression in tumour compared to healthy tissue
  • Acidity has effects on gene expression and immune cell behaviour
  • Leads to differentially spliced genes in tumours
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20
Q

how well perfused is a tumour?

A
  • hypoxic space in tumour where cells are dead
  • Tumour grows so fast so blood vessels can’t keep up – cells in the middle are dead – necrotic centre of the tumour
  • Dead ends in the vasculature can’t perfuse middle of tumour
  • No oxygen, no glucose, so cancers are dead in the middle
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21
Q

what model can we use to study cancer angiogenesis?

A

Rat-insulin promoter driving T-antigen (RIP-TAG mice) – genetically engineered mouse model
- Mice express viral T antigen (oncogene) under control of Rat-insulin promoter
- oncogene expressed in islets of langerhans
- Forms tumours in pancreas of mice – PDAC model – 5-7 weeks = hyperplastic islets, 7-12 weeks = angiogenic islets, by 14 weeks will have large tumours

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22
Q

how are islets changed in the RIP-TAG model?

A

Islets are naturally highly vascular to pump insulin into endocrine system

When a tumour is formed, there are lots more vessels and growth

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23
Q

what does carcinoma in situ mean?

A

cancer has not left original site as it hasn’t broken the basement membrane
- benign
- retained within primary basement membrane site
- unlikely to have metastasis

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24
Q

how does vascularisation impact prognosis?

A

The more vascularized the cancer, the poorer the prognosis
- high microvessel density predicts poorer survival
- low microvessel density provides favourable outcomes

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25
Q

what is vasculogenesis?

A

Vasculogeneis is formation of primary network in tissue
- in developing organism, endothelial progenitors (angioblasts)
- angioblasts invade developing tissues and differentiate in situ into primitive vascular network

26
Q

what is the origin of endothelial cells?

A

haematopoietic origin
- come from HSCs
- lineage of angioblasts

26
Q

what are the different modes of vessel formation in angiogenesis?

A
  • tip cell/sprouting angiogenesis (most important in tumours)
  • vasculogenesis - progenitors from BM differentiate to angioblasts which enter developing blood vessel
  • intersusception - vessel splits into two (vascular splitting)
  • vessel co-option - tumour grows along existing vessels, especially in lung cancer
  • vascular mimicry (tumour mimics endothelial cell) - less supported as it may not be non-thrombogenic
  • Tumour differentiation to endothelial cell - less supported
27
Q

how does lung cancer undergo angiogenesis?

A

vessel co-option:
- 30% lung is vessels - many blood vessels
- cancer can easily grow along vessels to obtain oxygen

28
Q

what is sprouting angiogenesis?

A

resting cells, palisade cells, differentiate to a tip cell in response to an angiogenic factor

29
Q

what causes a tip cell to form?

A
  • when an angiogenic factor hits a palisade cell, it changes its polarity so that a vessel cell becomes a tip cell via Notch-delta signalling
  • change in polarity means that the tip cell is different from the cells either side of it
30
Q

how does the tip cell undergo angiogenic outgrowth?

A

tip cell begins to sprout
- forms filopodia to move outwards
- growth factors such as VEGF cause the tip cell to extend
- (similar to axonal growth)

31
Q

how are new vessels formed in sprouting angiogenesis?

A

multiple vessels now have outgrowing tip cells:
- stalk cells proliferate behind the tip cell to push the tip cell forward
- fusion of two tip cells
- Tip cell filopodia anastamose with each other to form a new vessel by following the VEGF chemotactic gradient
- behind the developing tip are cells which from vacuoles, which fuse to create a lumen
- leads to formation of new blood vessel - stabilised by pericyte contacts

32
Q

what are the important angiogenic factors?

A
  • VEGF – stimulated by hypoxia, glucose deprivation and oxidative stress - important in tumours
  • FGFs - important in wound healing
  • Angiopoetin
33
Q

what 3 things can trigger the angiogenic signal?

A
  1. hypoxia
  2. oxidative stress
    - oxygen free radicals generated from glycolysis
  3. glucose deprivation
34
Q

what are the two key environments in the tumour and what do they cause?

A

low oxygen (hypoxia)
high acidity

these trigger the production of angiogenic factors such as VEGF

35
Q

how does VEGF expression differ across the tumour?

A

At edge of tumour, low at VEGF mRNA

Towards middle there is high mRNA expression in an attempt for survival

In centre, cells are dead due to lack of oxygen so no VEGF mRNA is present

as we move into the tumour, oxygen gets lower so more VEGF, until it hits necrotic centre

36
Q

how does HIF1 regulate hypoxia response genes?

A

HIF1a is a TF
- in presence of oxygen, proline hydroxylase binds oxygen to HIF1a prolines
- oxygen-HIF1a is recognised by VHL
- VHL ubiquitinates HIF1a and induces its degradation in the proteosome

in hypoxia, HIF1a is not hydroxylated, so is not recognised by VHL
- HIF1a can accumulate in the nucleus and complex with HIF1b to form a TF to transcribe angiogenic genes, including VEGF

this is crucial in normal cells for survival, but is exploited in tumours

37
Q

what is adrenomedullin?

A

similar to VEGF, induces angiogenesis
- mRNA of adrenomedullin increases under hypoxia

38
Q

how does adrenomedullin impact tumours?

A

injected tumour cells which were competent or deficient in adrenomedullin into mice:
- tumours which are competent in adrenomedullin have higher tumorigenicity (more tumours form) due to increased vessel density
- angiogenic factors can aid tumour formation

39
Q

how complex is angiogenesis?

A

very
- many different proteins implicated
- overlapping functions and redundancy
- many opportunities to block different pathways

40
Q

how can we mimic angiogenesis in the lab?

A

Aortic ring assay

Sponge angiogenesis assay

Window assay

41
Q

what is the aortic ring assay?

A
  • Chop rat aorta into rings and embed in gel matrix
  • Can see outgrowth of new vessels from the ring with a lumen – mimic angiogenesis
  • Useful for screening drugs that inhibit angiogenesis – in vitro assay that is reproducible and cheap
42
Q

what is the sponge angiogenesis assay?

A

Put small sponge under skin of mouse (subcutaneous) via small incision
- leave sponge for a couple of weeks
- fibroblasts grow into sponge and bring vessels with them
-FGF is present in the sponge
- Fibroblasts grew into sponge and formed vessel
- In presence of anti-angiogenic – no vascularisation of sponge

43
Q

what is the window assay?

A

Clamp skin of mouse between two metal plates, with glass window
- implant tumour within skin
- mouse is alive
- As tumour grows, new vessels grow into the tumour in real time
- can see blood flow and apply anti-angiogenics to see their effects of terminating blood flow

44
Q

what is VEGF?

A

Vascular endothelial growth factor
- Induced by hypoxia and glucose deprivation
- An endothelial specific growth factor
- Ubiquitously expressed in tumours, local VEGF level is a prognostic marker
- Mainly a stress-induced angiogenic factor

45
Q

what happens when VEGF is blocked by antibodies?

A

Antibodies to VEGF block tumour growth
- Leads to glioblastoma growth inhibition

46
Q

how can VEGF signalling be inhibited?

A

Monoclonal antibody to VEGF
- Bevacizumab / Avastin (humanised antibody to VEGF)

Soluble receptor
VEGF trap / aflibercept
- binds and sequesters VEGF

Small molecule inhibitors of VEGFR
- Sunitinib / sutent, sorafenib / nexavar

Antibody blocking binding of VEGF to its receptor
- IMC 1C11

47
Q

should anti-angiogenics be combined with cytotoxics?

A

Growth of tumours in mice:
- anti-VEGF leads to some inhibition of growth - avastin alone doesn’t do much
- Combine with cytotoxic drug – large inhibition of tumour growth

Most antiangiogenics used in combination in cytotoxics and cell cycle blockers

48
Q

how effective is avastin?

A

Avastin has been approved in US
- Clinical trial in CRC patients
- Avastin with triple cocktail of cytotoxics gave metastatic patients 6 months extra life
- NHS did not approve as it is too expensive for just one dose – 2 doses needed in those 6 months

49
Q

what are the side effects of avastin?

A

Adverse effects are mild compared with most chemotherapeutic agents
- Low-grade and manageable adverse effects include hypertension, proteinuria, nosebleed, upper respiratory infection, gastrointestinal symptoms and headache
- Rare and serious adverse effects include gastrointestinal perforations, hemorrhage and thrombolytic events

Side effects are likely to be due to the emerging role of VEGF in the normal maintenance of the vasculature

50
Q

what is the mechanism of action of avastin?

A

Inhibit blood vessel sprouting – only works when combined with chemotherapy - increases delivery of cytotoxic drug to the tumour:
- Because tumour has too much VEGF, avastin mops it up and stops sprouts to normalise the vessels and reduce branching and leakiness
- Cells differentiate into functional network
- Avastin increases blood flow in tumour
- vessels in tumour are now normal, so oxygen reaches tumours and they suddenly proliferate
- but cytotoxic drugs can now reach the tumour and kill the cancer

51
Q

how can mechanisms of resistance arise to VEGF therapy?

A
  • Tumours can produce alternative angiogenic factors (FGFs, IL8)
  • The hypoxic environment can select for more aggressive cancer cells better able to tolerate hypoxia and metastasise
  • Myeloid cells such as macrophages can be recuited, these may express the TIE-2 receptor, and these also produce pro-angiogenic factors.
  • Cancer-associated fibroblasts can produce PGDF
  • The CD11b GR1+ bone marrow-derived cells can produce an alternative pro-angiogenic factor known as BV8
52
Q

what is an alternative therapy to anti-VEGF?

A

targeting angiopoietin 2

53
Q

what is the angiopoietin (ANGPT)-TIE system?

A

ANGPT–TIE system is crucial for the angiogenic switch in tumours, and together with vascular endothelial growth factor A (VEGFA) promotes the initiation of angiogenesis and maturation of new vessels.
- The ANGPT–TIE system is also involved in inflammation, metastasis and lymphangiogenesis

54
Q

what are the key ligands/receptors in the ANGPT-TIE pathway?

A

ANGPT1 is a TIE2 agonist, and ANGPT2 functions as an antagonist or a partial agonist of TIE2 in different contexts.
- Both ANGPT1 and ANGPT2 have been shown to promote
or inhibit tumorigenesis in various settings

55
Q

what is the mechanism of ANGPT1 signalling?

A
  • ANGPT1 multimers bind to TIE2 on endothelial cells
  • TIE2 dimerises and is autophosphorylated
  • activated TIE2 binds and activates downstream effectors e.g. SHP2, GRB2 and PI3K
  • these activate eNOS to increase NO production
  • ANGPT1 can act as an anti-inflammatory cytokine
56
Q

what is the mechanism of ANGPT2 signalling?

A
  • ANGPT2 antagonises ANGPT1 to bind TIE2
  • mediates vascular permeability and primes for angiogenesis
  • ANGTP2 upregulates ICAM, E-selectin and VCAM on endothelial surface by blocking ANGPT1
57
Q

how do TIE1 and TIE2 antagonise one another?

A
  • TIE1 is activated by TIE2, which can feedback to inhibit ANGPT1-TIE2 interactions, thus antagonising ANGPT1
  • ANGPT2 can then induce inflammation
58
Q

what are the downstream effects of ANGPT1-TIE2?

A
  • ANGPT1-activated TIE2 recruits an NF-KB inhibitor (ABIN2) to inhibit inflammation, blocking expression of ICAMs, E-selectins and VCAMs on the endothelium
59
Q

is the ANGPT pathway being targeted?

A

ANGPT traps to sequester their signalling

AMG-386 is a peptibody whcih targets both ANGPT1 and ANGPT2
- reduces tumour blood flow and has modest anti-tumour activity
- more effective when i combination with paclitaxel

Cancer, Autoimmunity and Transplant Immunology (15 decks)

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