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BI3352: Cancer - Cellular and Molecular Mechanisms and Therapies > Angiogenesis 1 > Flashcards

Angiogenesis 1 Flashcards

1
Q

What specific molecule does Idelalisib target?

1 mark

A

PI3Kδ

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2
Q

Why is idelalib suitable for patient with follicular lymphoma?

2 marks

A
  • p110 delta isoform particularly expressed in lymphocytes and in the cancer has frequent mutations so want to target this isoform.
  • Delta used for specialised signalling in specialised cells
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3
Q

Would NVP-BKM120 theoretically work on this patient?

(from Q2)

2 marks

A

Yes – a pan class 1a pi3k inhibitor and hits all the isoforms alpha, beta and delta. So it would theoretically

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4
Q

Why not give the patient (Q3) NVP-BKM120?

1 mark

A

Too broad at targeting and would have too many off-target effects. Specifically affects glucose metabolism as impact AKT signalling

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5
Q

Outline the different structures in the basic histology of a blood vessel.

3 marks

A
  • Endothelial cell:
    • Basic bv cell (forms endothelium)
  • Basement membrane:
    • surrounds endothelium
  • Pericytes:
    • Perivascular cells i.e. related to vascular smooth muscle
    • Share basement membrane with endothelium
    • Abundant and tightly attached
    • Structural support
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6
Q

What is necrosis?

1 mark

A

Cell death by accident or trauma. Beyond ~100-200um of a blood vessel cells hypoxic and die of necrosis

Red Image: around capillaries oxygenated area and bright read areas are hypoxic

Blue image: granular staining indicates cells dying of necrosis

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7
Q

What causes necrosis?

1 mark

A

Hypoxia

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8
Q

What is angiogenesis?

1 mark

A

Formation of new blood vessels by ‘sprouting’ from new ones

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9
Q

Give some charactersitics of tumour blood vessels.

5 marks

A
  • Irregularly shapes
  • Pericytes loosely attached
  • Fail to stabilise properly
  • Dilated
  • Lack organisation and leaky
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10
Q

What happens in the avascular phase of a tumour?

1 mark

A

Dormant lesion and no angiogenesis

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11
Q

What happens in the vascular phase of a tumour?

1 mark

A

Activation of angiogenesis, allowing for tumour growth and spread

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12
Q

Give a basic overview of the processes involved in angiogenesis.

5 marks

A
  • Response to angiogenic stimulus, pericytes come off blood vessel destablizing it
  • BV dilates new vessels sprout and grow towards angiogenic stimulus
  • Mature will recruit pericytes back - not enough so not v tightly attatched
  • Vasculature v dynamic & instable
  • Process continues as areas become hypoxic
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13
Q

List a few examples of activators and inhibitors of angiogenesis.

6 marks

A
  • ACTIVATORS:
    • Matrix metalloproteinases (MMPs) - breakdown ECM so cells can pass basement membrane surrounding endothelium and have to sprout and grow
    • Nitric oxide - involved in vasodilation
    • VEGF - antiVEGF therapy with a humanized monoclonal antibody is an approved method to treat colon cancer and some types of nonsmall-cell lung cancers and metastatic breast cancer. best in combination with traditional chemotherapy or radiotherapy. ( Pelengaris et al 2013)
  • INHIBITORS:
    • Angiostatin
    • Endostatin
    • Thrombospondin 1 &2
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14
Q

What is HIF?

4 marks

A
  • Hypoxia-inducible factor
  • Made of one HIF-1a and one HIF-1b subunit
  • Both^^ mRNA constittutively expressed
  • Regulated at HIF-1alpha protein level
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15
Q

What does HIF do?

2 marks

A
  • Drives transctiption of pro-oncogene genes target is VEGF as increases distribution of oxygen
  • HIF1alpha levels regulated by oxygen levles - normoxic = 20% O2 so HIF1a levels down and by VHL tumour suppresor protein
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16
Q

What happens in a normoxic environment?

2 marks

A
  • O2 levels activate prolyl 4 hydorxylase this modiefies specific prolines on HIF1 alpha
  • VHL protein binds to hydroxylated proline promoting ubiquitynylation and degradation of HIF1a protein
17
Q

What happens to HIF1alpha in a hypoxic environment?

1 mark

A
  • Prolyl hydroxylase is not activated and HIF1alpha is present to form complete transcription factor
18
Q

What does VHL do to HIF1 alpha in a normoxic environment?

1 mark

A
  • VHL recruits range of proteins to site so alpha subunit is polyubiquitinated and then targeted for degradation by proteosomal pathway
  • No alpha subunit present no degradation
19
Q

What is a therapeutic way to target HID1alpha?
1 mark

A

Enhance HIF1alpha protein degradation and so prevent HIF binding to gene promoter and inhibiting HIF1alpha production

20
Q

How does the expression of the HIF-1a isoforms change over time?
3 marks

A
  • 3 isforms - HIF - 1,2,3alpha
  • HIF1a involved in acute response to hypoxia and increases and falls after 12 hrs
  • Hypoxia sustained get expression of 2 and 3 - switch between isoforms regulated by microRNAs
  • need to target all 3
21
Q

Repeat 3x the next slide on oncogenes and their mechanism of pro-angiogenic activity

A

Bcl-2

VEGF upregulation

Fos

VEGF upregulation

Jun

VEGF upregulation, thrombospondin downregulation

Wnt

Increased VEGF

p53

VEGF upregulation, thrombospondin downregulation

VHL

Increased VEGF

Rb

Decreased thrombospondin

Ras

VEGF upregulation, thrombospondin downregulation

22
Q

What is VEGF and what does it do?
3 marks

A
  • Ligand essential for tumour development
  • Produced throughout tumour life cycle
  • Isoform A can generate abnormal blood vessels
23
Q

What does the VEGF family bind to respectively and what do they regulate?
3 marks

A
  • VEGF A can bind to receptor VEGFR1 and VEGFR2
  • VEGF C & D can bind to recptors VEGFR2 & VEGFR3
  • Family regulates lymph angiogenesis as tissue sprouts and grows in the same way
24
Q

Which is the most important VEGF isoform for tumourogenesis and angiogenesis?

1 mark

A

VEGF A

25
Q

In what forms does the VEGF A isoform exist?
3 marks

A
  • Different spliced variants that can bind to VEGFR1/2 and be cleaved by plasmid
  • Differ in C-terminal where they bind heparin in ECM
  • Heparin binding site determines if bind to ECM and how strong
26
Q

Which variant of VEGF A do tumours produce the most and why?

3 marks

A
  • VEGF variant 165:
    • Can be free and bound to ECM
    • Provide short and long range guidance for new molecules - can compensate for other two variants
27
Q

What are the other 2 variants of VEGF A and why aren’t they produced as much as VEGF165?

6 marks

A
  • VEGF121:
    • Doesn’t bind heparin sulfate and freely diffusible
    • Provide long range guidance for developing blood vessels
  • VEGF189:
    • Strongly bind heparan sulphate and ECM
    • Provide short range guidance for developing blood vessels

VEGF165 - good mix of the two

28
Q

How does a distinct release of bound VEGF to ECM occur in a tumour to start angiogenesis?

4 marks

A
  • Pre-malignant cells don’t see increase in VEGF or VEGFR
  • (7-12wk model) - cells switch on angiogenesis are malignant and growing
  • Islet cells w/ excess proliferation send signal to bone marrow, which sends signal to macrophages then to islets
  • Immunce cells release MMPs to cleave ECM bound VEGF and fragment will go to bind to VEGFR - isn’t increased in islets and trigger angiogenesis
29
Q

What is the placental growth factor?

3 marks

A
  • Normally confined to placenta but can be overexpressed in tumours
  • Binds to VEGFR-1
  • Can potentiate VEGF-A activity (by binding to VEGFR-1), s_timulates detachment of pericytes and activate pro-angiogenic genes_
30
Q

What are VEGFRs?

1 mark

A
  • Receptor tyrosine kinases that possess split kinase in intracellular domain
31
Q

What is a split kinase?
1 mark

A

Additional kinase baove main kinase that doesn’t make them operate in any different way

32
Q

What is VEGFR-1?

2 marks

A
  • TRK weakly activated by VEGF-A but binds to it with strong affinity
  • Postulated to be a decoy receptor as receptor 1 binds to VEGF
33
Q

What is VEGFR-2?

2 marks

A

TRK strongly activated by VEGF-A weakly binds ligands

Overexpressed in tumour cells

34
Q

Does PLGF bind to VEGFR-1 or VEGFR-2?

2 marks

A
  • VEGFR-1
  • If lots in tumour will bind to it leaving less receptor available to bind to VEGF-A
35
Q

What are neuropilins?

2 marks

A
  • Apart of VEGF R family
  • Very short cytoplasmic tails and act as co-receptors for VEGF so VEGF a will bind neuropilin and will present ligand in way to VEGFR2
36
Q

How is tumourigenic angiogenesis promoted by VEGF-A through VEGFR-2?

6 marks

A
  • Signalling via VEGFA through VEGFR2 (165 variant)
  • VEGFA dimeric ligand - get transphoshporylation of tyrosines on receptors
  • Signalling promotes production of nitric oxide for dilation of BV
  • RAS/MAP/Kinase promote endothelial cell proliferation
  • For migration signal pormotes migration (from CDC42)
  • Signalling via AKT will enhance cell survival by inhibiting apoptosis

BI3352: Cancer - Cellular and Molecular Mechanisms and Therapies (7 decks)

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