18 - Tumor Angiogenesis Flashcards
What are the four major types of blood vessels?
Arteries - away frmo heart and “branch”, “diverge”, “fork”
Capillaries
Veins - toward the heart and “join”, “merge”, “converge”
Lymphatics
What are general characteristics of vessels? What do large vessels have?
Tube with a hollow lumen filled with blood or lymph fluid.
Inner endothelial cells and outer smooth muscle cells
Larger vessels have valves to control flow.
How does the structure of arteries, veins, and capillaries differ?
Arteries: have an internal elastic lamina between the intima and the media and an external elastic lamina between the media and the tunica externa (adventitia).
Veins: no elastic lamina
Capillaries: no media
What is angiogenesis? What is vasculogensis?
Angiogensis: sprouting of vessels from established vasculature - sometimes referred to in the context of remodeling vasculature
Vasculogenesis: de novo differentiation of precursor cells to differentiated endothelial cell, and assembly of these endothelial cells into tubes (vessels) - often associated with embryonic development.
What are the steps in vessel formation?
- Vasculogenesis: blood islands and fusion to form primary capillary plexus
- Angiogenesis: differentiation of capillaries, arteries, and veins.
- Lymphangiogenesis: formation of lymphatic capillaries and collecting ducts.
Describe vessel formation in development and for adults? What are some pathological examples of this?
Embryonic vasculature invovles both vasculogenesis and angiogenesis.
In adult physiology angiogensis is needed for wound healing and female reproduction
Pathological conditions: tumors, age-related macular degeneration (wet kind)
What is the appearance of abnormal vasculature?
- Vessels are leaky, tortous, and dilated.
- Haphazard pattern of interconnection.
- Endothelial cells lining the vessels have aberrant morphology
- Pericytes are loosely attached or absent
- BM is thick, thin, or absent
What are six different wants to accomplish tumor vascularization?
- Sprounting angiogenesis
- Vasculogenesis from BM
- Vascular mimicry: tumor cells change identity and become endothelium to line vasculature
- Intussusception (vessel splitting)
- EC differentiation: cancer stem-cell likes cells differentiate
- Vessel cooption: tumor cells coopt preexisting vessels
Describe the switch from an avascular to a vascular state for a tumor? What is this called and when does it occur?
Angiogenic switch: discrete step that can occur at different stages in the tumor progression pathway depending on the nature of the tumor and its microenvironment.
Normally occurs at initial stage when the tumor is 2 mm in size.
What occurs during the angiogenic switch?
- Periveascular detachment and vessel dilation
- Onset of angiogenic sprouting
- Continuous sprouting and maturation; recruitment of perivascular cells
- Tumor vasculature
What are two hypothesis as to what triggers the angiogenesis switch?
- Hypoxia - lack of oxygen
- Matrix metalloproteinase-9 upregulation (Rip-Tag model of islet cell tumor progression)
Tumor vascular bed is highly ______ and ______.
unstructured and chaotic
Vessel growth homeostasis is maintained by what?
The balance between pro-angiogenic and anti-angiogenic molecules
Vessel formation mimics what?
Axon guidance.
Vessels and nerves grow similarly.
During angiogenesis, which cells proliferate and which do not?
Stalk cells proliferate while Tip cells do not.
What is the structure of a tip cell? What does it have and what inducecs it? What is it’s function?
- Single, highly polarized endothelial cells with numerous actin rich filopodia protrustions.
- Lacks vascular lumen.
- Induced by VEGF-A and has VEGFR2 on filopodia.
- Specialised for guided migration, rarely proliferates.
What is the structure of a stalk cell? What does it have and what inducecs it? What is it’s function?
Proliferates when stimulated with VEGF-A.
Forms vascular lumen and establishes firm adherens junctions.
Deposits basement membrane and can be induced to become new tip cells.
What are the basic components of the Notch signaling pathway?
Ligand on endothelial sending/Tip cell binds the Notch receptor on an endothelial recieving/stalk cell.
This causes downstream signaling such that NICD translocates to the nucleus and activates transription.
Describe the induction of sprout and tip cell selection (first steps in forming a stable vessel)?
- Select cell that expresses the most VEGF receptor 2 for tip cell
- Tip cell induces delta ligand like 4, which binds notch
- Shut down nearby cells from making VEGFR - these will be the stalk cells
Describe tip cell guidance and stalk elongation that occurs during angiogenesis?
- Tip cell starts to migrate and monocytes secrete things to help make the connections.
- Stalk undergoes lumen formation and elongation.
- Cells must collectively migrate and other cells must be recruited.
What happens after two tip cells meet and form a new vessel in angiogenesis?
Maturation and quisense of phalanz cells
What was the concept behind 1st gen anti-angiogenic strategies?
They were VEGF-centric and focused on binding VEGF in order to prevent tumor angiogenesis.
What is metronomic chemotherapy?
Idea is to give a low dose of chemo each day without giving breaks in therapy after 2 weeks (standard regiment).
Also, dose is lower than maximum tolerable dose (MTD).
