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FPP Block 1 > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

Describe vessels

A
  • a tube with a hollow center (lumen)
  • lumen is filled with blood or lymph fluid
  • inner epithelial and outer smooth muscle cells
  • larger vessels have valves to control flow
  • large vessels to small vessel to capillaries
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2
Q

WHat is angiogenesis?

A

sprouting of vessels form established vasculature

sometimes refered to in the context of remodeling vasculature

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3
Q

What is vasculogenesis

A

de novo differentiationof precursoe cells to differentiated endothelial cell and assembly of these endothelial cells into tubes (vessels)

often associated during embryonic development

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4
Q

what are two two types of vessel formation in developemtn

A

vasculogenesis and angiogenesis

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5
Q

what is the vasculature development in adults

A

angiogenesis

  • adult physiology (wound healing, female reproduction)
  • pathological conditions-tumors, age related macular degeneration
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6
Q

what are some characteristics of abnormal vasculature?

A
  • blood vessels are leaky, tortuous and dilated
  • they have haphazard pattern of interconnection
  • endothelial cells lining the vessels have aberrant morphology
  • pericytes are loosely attached or absent
  • basment membrane thick, thin or absent
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7
Q

What are the numerous ways to accomplish tumor vascularization?

A
  • sprouting angiogenesis
  • vasculogenesis
  • vascular mimicry
  • intussception
  • EC differentiation
  • vessel cooption
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8
Q

WHat is angiogeneic switch?

A

a discrete step in tumor development that can occur at different stages in tumor progression pathway depending on the nature of the tumor and its microenvironment. (usually at initial stages often due to lack of oxygen)

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9
Q

tumor growth is _________ dependent

A

angiogenesis.

some people think that if you block the angiogeneic switch from occuring you could leave the tumor in the dormant stage and stop it from growing, letting the immune system handle it.

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10
Q

What are the 2 hypothesis of what triggers angiogenic switch?

A
  1. Hypoxia: often a lack of oxygen. the distance of a tumor cell from vasculature is associated with lack of oxygen and lower (more acidic) pH.
  2. MMP
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11
Q

what helps maintain angiogeneic homesotasis

A

balance between pro and anti angiogenic regulators

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12
Q

WHat are the 2 processes by which vessels are formed

A

vaculogenesis and angiogenesis

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13
Q

tumors underg a switch from an avascular state to vascular ststae, which signals _________

A

the growth of new blood vessels

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14
Q

the tumor vascular bed is ___________

A

high unstructured and chaotic

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15
Q

vessel formation mimics______

A

axon growth!

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16
Q

during angiogenesis which eclls proliferate and which cells do not

A

endothelial stalk cells proliferate but tip cells do not

17
Q

Describe the tip cell?

A
  • single highly polarized endothelial cells
  • numerous actin rich filopodia protrusions
  • induced by VEGF-A
  • VEGFR2 on filopodia
  • lacks a vascular lumen
  • increased mRNA levels of various markers
  • specialized for guided migration
  • rarely proliferates
18
Q

Descibe the stalk

A
  • proliferate when stimulated with VEGF-A
  • form vascular lumen
  • establish firm adherens junctions
  • deposit basement membrane
  • express higher levels of markers
  • can be induced to become new tip cells
19
Q

what are the molcules/pathways of interest in vascular biology?

A

Vascular endothelial growth factor (VEGF)

Notch

20
Q

what are the two moleculecular signaling pathways studied in tip vs stalk specification

A

VEGF pathway Notch signaling pathway

21
Q

How does VEGF signaling

A

tyrosine kinase receptors that get phosphorylated when VEGF binds

22
Q

How does notch signlaing work

A

cell surface receptor and ligand on the surface of a differnet cell. binding leads to conformation change and enzyme cleavage which releases intracellular domain that translocates to the nucleus and actiavtes transcription

23
Q

What are the steps to forma a stable vessel

A
  1. indution of sprout
  2. tip cell selection
  3. tip cell guidance and stalk elongation
  4. maturation ans quiescence of phalanx cells
24
Q

how does tip/stalk selection occur

A

one cell develops VEGFR2 and that is the tip. the tip cell induces delta ligand like 4 which binds notch. that shuts the other cell down from being able to make VEGFR this is the stalk

***VEGF and notch signaling work together to co-ordinate tip vs stalk formation. then a series of intricate steps occurs in a coordianted fashion to facilitate vessel assembly

25
Q

what was the 1 generation of anti-angiogenic stragtegies? did it work?

A

anti-VEGF

no it wasn’t primising

26
Q

what is metronomic chemotherapy

A

the idea is to give low dose chemo each day without giving breaks in therapy after 2 weeks (standard regimen)

also dose is lower than maximum tolerable dose.

typically chemo is high dose with breaks, this is continous low dose

27
Q

does metronomic chemotherpay work?

A

yes!

28
Q

the logic of chemotherpay is changeing what is a proposed mechanism?

A

doing both metronomic dosing at lower levels in combination with other agents

**** the best way may be two drugs low dose at the same time

29
Q

what is the possible mechanism of the anti-angiogenic basis of metronomic chemo

A

vessile normalization

30
Q

describe the tumor vascular bed

A
  • chaotic
  • pericytes are uneven or missing
  • structural abnormalities contribute to spatial and temoral heterogeneity in tumor blood flow
  • solid pressure generated by proliferating tumor cells compress intra-tumor blood and lympatic vessels, which further impairs blood flow
  • interstitial hypertension (elevated hydrostatsic pressure on outside of blood vessel)
  • hypoxia and acidosis
31
Q

What is the net result in terms of treatability of the chaotic nature of the tumor vascular bed

A
  • interference with delivery of therapeutics to tumors
  • hyoxia renders tumor cells resistant to radiation and cytotoxic drugs
  • selection of more malignant cells with increased metastatic potential
  • immune cell fucntion compromised in this environment
32
Q

do if the chaotic nature of the tumor vasculature inpeedes treatability what do we do?

A

Vessel normalization! correct the structure!

33
Q

what is vessel normalization

A

to correct the structure and function of tumor vessels-“normalize it”, we would then be able to deliver drugs and perhaps even contain the tumr from spreading. essentially make the tumor vesself better first before targeting it!

34
Q

drug dose and schedule will provide a ______

A

normalization window

35
Q

will tumor growth accelerate during this window?

A
  • tumor heterogeneity will balance out the normalization effects-so collectively no growth
  • transient normalization will mean grwing tumor cells are now susceptible to chemo drugs better
  • cancer cells also depend on the same factors as endothelial cells for survival, therefore now anti-angiogenetics can access tumor cells better!
36
Q

WHat is the TCR concept?

A
  • short term sacrific for long term gain!
  • during radiation of tumors, concurrent methods are used to improve oxygenation
  • checkpoint protein inhibitors (PD-1) concurrent treatment with DNA damaging agents (radiation) is proposed to enhance PD-1 inhibition efficacy
37
Q

what is a non-oncology application for anti-angiogeneic agents

A

AMD (wet) leaky blood vessels

38
Q

Hw do yu treat wet AMD

A

anti-VEGF

39
Q

________________ are partly responsible for the effectiveness of metronomic regimen

A

endothelial cells

FPP Block 1 (18 decks)

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