Angiogenesis

Question 1

Describe vessels

Answer 1

• 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

Question 2

WHat is angiogenesis?

Answer 2

sprouting of vessels form established vasculature

sometimes refered to in the context of remodeling vasculature

Question 3

What is vasculogenesis

Answer 3

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

often associated during embryonic development

Question 4

what are two two types of vessel formation in developemtn

Answer 4

vasculogenesis and angiogenesis

Question 5

what is the vasculature development in adults

Answer 5

angiogenesis

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

Question 6

what are some characteristics of abnormal vasculature?

Answer 6

• 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

Question 7

What are the numerous ways to accomplish tumor vascularization?

Answer 7

• sprouting angiogenesis
• vasculogenesis
• vascular mimicry
• intussception
• EC differentiation
• vessel cooption

Question 8

WHat is angiogeneic switch?

Answer 8

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)

Question 9

tumor growth is _________ dependent

Answer 9

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.

Question 10

What are the 2 hypothesis of what triggers angiogenic switch?

Answer 10

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

Question 11

what helps maintain angiogeneic homesotasis

Answer 11

balance between pro and anti angiogenic regulators

Question 12

WHat are the 2 processes by which vessels are formed

Answer 12

vaculogenesis and angiogenesis

Question 13

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

Answer 13

the growth of new blood vessels

Question 14

the tumor vascular bed is ___________

Answer 14

high unstructured and chaotic

Question 15

vessel formation mimics______

Answer 15

axon growth!

Question 16

during angiogenesis which eclls proliferate and which cells do not

Answer 16

endothelial stalk cells proliferate but tip cells do not

Question 17

Describe the tip cell?

Answer 17

• 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

Question 18

Descibe the stalk

Answer 18

• 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

Question 19

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

Answer 19

Vascular endothelial growth factor (VEGF)

Notch

Question 20

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

Answer 20

VEGF pathway Notch signaling pathway

Question 21

How does VEGF signaling

Answer 21

tyrosine kinase receptors that get phosphorylated when VEGF binds

Question 22

How does notch signlaing work

Answer 22

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

Question 23

What are the steps to forma a stable vessel

Answer 23

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

Question 24

how does tip/stalk selection occur

Answer 24

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

Question 25

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

Answer 25

anti-VEGF no it wasn't primising

Question 26

what is metronomic chemotherapy

Answer 26

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

Question 27

does metronomic chemotherpay work?

Answer 27

yes!

Question 28

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

Answer 28

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

Question 29

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

Answer 29

vessile normalization

Question 30

describe the tumor vascular bed

Answer 30

* 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

Question 31

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

Answer 31

* 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

Question 32

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

Answer 32

Vessel normalization! correct the structure!

Question 33

what is vessel normalization

Answer 33

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!

Question 34

drug dose and schedule will provide a \_\_\_\_\_\_

Answer 34

normalization window

Question 35

will tumor growth accelerate during this window?

Answer 35

* 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!

Question 36

WHat is the TCR concept?

Answer 36

* 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

Question 37

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

Answer 37

AMD (wet) leaky blood vessels

Question 38

Hw do yu treat wet AMD

Answer 38

anti-VEGF

Question 39

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ are partly responsible for the effectiveness of metronomic regimen

Answer 39

endothelial cells