Angiogenesis

Question 1

Mobilization process, assembly, alignment and fusion to form vasculature

Answer 1

Vasculogenesis

Question 2

Vessels start from existing vasculature

Answer 2

Angiogenesis

Question 3

How is endothelial cell structure relevant for angiogenesis?

Answer 3

Endothelial cells have a large nucleus and processes that envelop toward one another to create a lumenal space –> become a bv

Question 4

Explain the process of angiogenesis.

Answer 4

1. Selection of sprouting ECs: modulation of EC contacts, change in polarity
2. Sprout outgrowth and guidance: maintenance of junctions, deposition of new ECM, EC proliferation
3. Sprout fusion and lumen formation: stalk cell proliferation, vacuole formation and fusion, TIP cells encountering repulsion/adhesion
4. Perfusion and maturation: stabilization of EC-EC adhesion, decrease EC proliferation

Question 5

What is a signal for angiogenesis?

Answer 5

Hypoxia.

Tumor cells can sustain on their own for ~2 mm radius but then it needs to recruit more metabolic products

Question 6

How does the signal to proliferate occur when a tumor gets large enough?

Answer 6

HIF-1alpha gets stimulated, dimerizes with HIF-1beta, goes to the nucleus and transcribes genes (VEGF: induces surrounding endothelial cells to start proliferating, migrate and go to tumor)

Question 7

How does tumor vasculature differ from normal vasculature?

Answer 7

Tumor vasculature = Chaotic
They secrete many more growth factors than a normal endothelial cell
Tumor vessels do not have smooth muscle cells that surround them.
There are gaps in tumor vasculature used to leak out contents, escape and metastasize

Question 8

How are the lymphatics different in tumor beds?

Answer 8

They aren’t working very well so there is a problem with intratumoral pressure – this can prevent the delivery of chemotherapeutics.

Question 9

Why do only a subset of islet cells trigger angiogenesis?

Answer 9

Pancreatic islets have lots of VEGF at all times but are only angiogenic at late stages. MMP-9 is secreted by cells in bone marrow (mast cells, macrophages) and releases the VEGF and makes it available to tumor cells.

Question 10

Name some common angiogenic activators.

Answer 10

VEGF, FGF-1

Question 11

Name some common angiogenic inhibitors.

Answer 11

Thrombospondin, angiostatin, endostatin, collagen IV fragments

Question 12

What is VEGF really good at?

Answer 12

Potent permeability inducer. 50,000 times more potent than histamine

Question 13

What are two main VEGF receptors?

Answer 13

VEGF2: tyrosine phosphorylation residues, phenotype induced in cells d/t very specific regulation
VEGF3: Particularly on lymphatic vessels (lymphangiogenesis)

Question 14

Explain the role of NOTCH.

Answer 14

NOTCH is tether in the cell and when cleaved it binds to ligands on other cells and leads to the intracellular domain entering the nucleus and turning on transcription. Plays a role in TIP-Stalk cell interaction.

Question 15

What are some benefits of pursuing anti-angiogenic therapy?

Answer 15

You are targeting a genetically stable population (endothelial cells) and not a genetically unstable tumor cell.
Uses naturally occurring proteins in the body – high tolerance, less SE.
Easy accessibility for drugs – circulation.
Targets origin of metastasis

Question 16

What are some of the different strategies to target VEGF?

Answer 16

Anti-VEGF antibodies (avastin) – used for ocular angiogenesis in macular degeneration.
Soluble VEGF receptors – binds to lianas with higher affinity than antibodies.
Small molecules to prevent signaling.
Peel off pericytes and target with PDGF inhibitor and cells are more sensitive to chemotherapy.

Question 17

What are some of the mechanisms of resistance to anti-angiogenic therapy?

Answer 17

Vascular mimicry – tumor cells start making their own vessels
All the cells that play a role in the tumor bed: endo, BM, ECM, pericyte, fibroblast, lymphatic cell, neutrophil, macrophage, mast cell etc – difficult to control/target all!