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Oncology > Lecture 5: tumor angiogenesis > Flashcards

Lecture 5: tumor angiogenesis Flashcards

1
Q

Two basic components of the circulatory system

A

blood vascular system and lymphatic vascular system

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2
Q

Blood vascular system

A

circulates blood from the heart throughout the body and back through the kidney, liver and lung for cleaning and re-oxygenation.

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3
Q

lymphatic vascular system

A

collects fluid (e.g. leaked blood) from tissues and recycles it onto the bloodstream, after the fluid first flows through a series of lymph nodes involved in immune surveillance of tissues

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4
Q

what contain lymph nodes ?

A

immune cells

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5
Q

In what part of the vascular system does the cell get the oxygen?

A

the (lymphatic) capillaries

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6
Q

Tissue interface :

A

the blood micro-vasculature (capillaries)

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7
Q

The tubes of the vascular system are composed of..

A

‘blood endothelial cells’ (BEC)

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8
Q

Blood vessels have associated periendothelial support cells, of two prominent types:

A

pericytes and smooth muscle cells (SMC)

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9
Q

Which types of blood vessels have pericytes ?

A

all of them

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10
Q

Which types of blood vessels have more layers of SMC and which have less ?

A

Large vessels have layers of SMC.
- more : arteries
- less : veins

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11
Q

BEC =

A

blood endothelial cell

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12
Q

The tubes of the lymphatic system are composed of…

A

a developmentally related but functionally distinctive lymphatic endothelial cell (LEC)

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13
Q

Can we find pericytes or smooth muscle support cells on the tubes of the lymphatic system ?

A

Nope

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14
Q

Lymphatic vasculature has to..

A

allow the fluid to enter easily (thus no pericytes or SMC)

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15
Q

Structure of blood capillaries

A

continuous basement membrane and associated pericytes, and the BECs form tight and adherence junctions.

-> robust structure, no leakiness

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16
Q

Structure of lymphatic vessels

A

thin walled and have a relatively wide lumen.

The endothelial cells of lymphatic capillaries lack tight junctions.

The LECs partly overlap, forming valve-like openings, which allow easy access for fluid, macromolecules, and cells into the vessel lumen.

Lymphatic capillaries lack pericytes and have a fragmentary basement membrane.

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17
Q

When are vessels produced ?

A

during embryonic development

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18
Q

What are the two mechanisms by which the vessels are produced ?

A

vasculogenesis and angiogenesis

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19
Q

Vasculogenesis - what is it ?

A

the birth of new endothelial cells from yolk-sac-derived stem cells, and their assembly into tubes

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20
Q

Angiogenesis - what is it ?

A

the sprouting of new vessels from preexisting vessels

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21
Q

Vasculogenesis - the three step of its process

A
  1. Hemato-angioblast progenitor
  2. Endothelial cells
  3. New blood vessel
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22
Q

When is angiogenesis happening and what are the exceptions ?

A

only during growth of an organ.

Exceptions : repair of tissue, pregnancy, lot of sport (muscle growth), menstruations

23
Q

Angiogenesis - the three step of its process

A
  1. Quiescent, normal blood vessel
  2. Angiogenic activators induce proliferation. Basement membrane & ECM degradation. Pericyte detachment. BEC sprouting, proliferation & migration.
  3. Formation & closure of capillary tube. Pericyte attachement. Creation of a functional new blood vessel
24
Q

How does hypoxia stimulate angiogenesis ?

A

through stabilization of HIF1a, which induces VEGFA transcription

25
HIF1a (hypoxia-inducible factor 1a)
is **constitutively expressed** but its stability and activity are **regulated by oxygen levels**
26
Prolyl hydroxylases (PHDs) - role
hydroxylate HIF in the presence of oxygen
27
pVHL - role
Von Hippel-Lindau (a tumor suppressor mutated in sporadic kidney cancer), promotes HIF1alpha degradation in the presence of oxygen
28
ATTENTION OUBLIEZ PAS DE REVISER LE PATHWAY DE LA SLIDE 16
BISOU
29
HIF1a, prolyl hydroxylases, pVHL - explain their role
**HIF1a** (hypoxia-inducible factor 1a) is constitutively expressed but its stability and activity are regulated by oxygen levels **Prolyl hydroxylases** (PHDs): hydroxylate HIF in the presence of oxygen **pVHL** : Von Hippel-Lindau (a tumor suppressor mutated in sporadic kidney cancer), promotes HIF1alpha degradation in the presence of oxygen
30
What is the key receptor for VEGFA in endothelial cells ?
VEGFR2
31
What does VEGFA induce ?
directional growth of blood vessels
32
How does VEGFA promote disruption of endothelial cell junctions ?
by targeting VE-Cadherin (a junctional protein) (il y a une phosphorilation dans l'histoire)
33
How do endothelial cells and pericytes associate ?
Platelet-derived growth factor-B (**PDGF-BB**) from endothelial cells binds to **PDGF-Rβ** on pericytes, recruiting them to blood vessels. Angiopoietin-1 (**Ang1**) from pericytes binds **Tie2** on endothelial cells, promoting vascular stability.
34
What can overrule the quiescence of pericyte-endothelial interactions to induce angiogenesis ?
pro-angiogenic factor such as VEGFA
35
In what is Ang1/Tie2 signaling implicated ?
recruiting pericytes and enabling vessel maturation; Ang-2 blocks this function
36
What happens : - in presence of Ang2 and VEGFA ? - in presence of Ang2 ?
- angiogenesis - in some cases, promote vessel regression
37
Cells in tissues must be within ... of a capillary to receive oxygen and nutrients by diffusion
100 microns
38
Nests of tumor cells cannot grow beyond a few hundred microns in diameter without...
inducing angiogenesis and becoming vascularized
39
Tumor growth is dependent of ?
angiogenesis
40
6 histological signs of tumor angiogenesis
1. Endothelial cell proliferation 2. Endothelial cell elongation and sprouting from established vessels 3. Increased branching of blood vessels 4. Dilatation of vessels 5. Micro-hemorrhaging 6. Variable and less intimate coverage by pericytes
41
Particularities of the angiogenic switch
Can **occur at distinct stages** during tumorigenesis (e.g. premalignant lesions or later stages) It is dependent on **tumor type** and the **microenvironment**
42
Angiogenic inhibitor and 2 activators
Inhibitor : Ang1 Activators : VEGFA, Ang2
43
If VEGFA blocked ...
limit tumor growth
44
5 hallmarks of the tumor vasculature
* Irregularly shaped, tortuous, dead ends * Chaotic organization (no defined arterioles, venules etc.) * Leaky, hemorrhagic * Pericytes less abundant and more loosely associated with the vasculature * Cancer cells can be integrated in the vessel wall
45
Features of tumor blood vessels
No distinct arteries and veins, irregular morphology, uneven pericyte coverage (immature, unstable, leaky) -> poorly functional, leaky, provide inadequate oxygen and nutrient levels to the tumor mass
46
The aberrant and dysfunctional tumor vasculature promotes...
a chronic “wound healing response” that sustains tumor progression
47
Uneven pericyte coating, endothelial gaps and labile endothelial junctions cause..
significant **accumulation of fluid** in the tumor and **promote inflammation**
48
The four phases of the healing of a wound (normal tissues)
Hemostasis (stop blood flow), inflammatory phase (24h), proliferative phase (72h), remodeling phase (weeks/months)
49
Hemostasis phase - what happens ?
When blood vessels are injured, the damaged endothelium exposes **collagen**, causing platelets to activate and stick together. Tissue factor (TF) starts a **chain reaction** that turns **prothrombin into thrombin**. Thrombin then converts **fibrinogen into fibrin**, which forms a mesh that traps more platelets — creating a **blood clot**.
50
Inflammation and angiogenesis phases - what happens ?
Platelets release growth factors that attract **macrophages**, which secrete VEGFA. -> angiogenesis. **Fibroblasts** are also attracted and secrete VEGFA -> angiogenesis.
51
What is the mechanism of action of bevacizumab ?
-- it is a monoclonal antibody that **blocks VEGFA** through binding and sequestration, thus preventing its binding to the receptor (mainly VEGFAR2) -- it **blocks VEGFA-induced angiogenesis** -- **limits the vascularization of tumors**
52
What does bevacizumab therapy improve and how ?
Response to chemotherapy. Reducing VEGFA levels in tumors may make the **blood vessels less angiogenic** and **more normal**. The remaining cells may be more functional, allowing for **better delivery of chemotherapy**.
53
What is happening for patients treated with chemotherapy + bevacizumab and why ?
4 month longer 50% survival rate but eventually die at the same time. Tumors may become **more invasive**, owing to increased hypoxia. Cancer cells may look for a better soil to grow. -> Tumors **grow less initially**, they become **more aggressive with time**, therefore nullifying the initial benefits.

Oncology (9 decks)

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